Processes and intermediates for the preparation of 1′-substituted carba-nucleoside analogs

ABSTRACT

Provided are processes and intermediates for the syntheses of nucleosides of pyrrolo[1,2-f][1,2,4]triazinyl and imidazo[1,2-f][1,2,4]triazinyl heterocycles of Formula I.

This application is a Continuation of U.S. patent application Ser. No.12/886,248, filed on Sep. 20, 2010, claiming the benefit under 35 U.S.C.119(e) of U.S. provisional application 61/244,299 filed Sep. 21, 2009which is herein incorporated by reference in its entirety for allpurposes.

FIELD OF THE INVENTION

The invention relates generally to methods and intermediates forpreparing compounds with antiviral activity, more particularly methodsand intermediates for preparing nucleosides active against Flaviviridaeinfections.

BACKGROUND OF THE INVENTION

Viruses comprising the Flaviviridae family comprise at least threedistinguishable genera including pestiviruses, flaviviruses, andhepaciviruses (Calisher, et al., J. Gen. Virol., 1993, 70, 37-43). Whilepestiviruses cause many economically important animal diseases such asbovine viral diarrhea virus (BVDV), classical swine fever virus (CSFV,hog cholera) and border disease of sheep (BDV), their importance inhuman disease is less well characterized (Moennig, V., et al., Adv. Vir.Res. 1992, 48, 53-98). Flaviviruses are responsible for important humandiseases such as dengue fever and yellow fever while hepaciviruses causehepatitis C virus infections in humans. Other important viral infectionscaused by the Flaviviridae family include West Nile virus (WNV) Japaneseencephalitis virus (JEV), tick-borne encephalitis virus, Junjin virus,Murray Valley encephalitis, St Louis enchaplitis, Omsk hemorrhagic fevervirus and Zika virus. Combined, infections from the Flaviviridae virusfamily cause significant mortality, morbidity and economic lossesthroughout the world. Therefore, there is a need to develop effectivetreatments for Flaviviridae virus infections.

The hepatitis C virus (HCV) is the leading cause of chronic liverdisease worldwide (Boyer, N. et al. J Hepatol. 32:98-112, 2000) so asignificant focus of current antiviral research is directed toward thedevelopment of improved methods of treatment of chronic HCV infectionsin humans (Di Besceglie, A. M. and Bacon, B. R., Scientific American,October: 80-85, (1999); Gordon, C. P., et al., J. Med. Chem. 2005, 48,1-20; Maradpour, D.; et al., Nat. Rev. Micro. 2007, 5(6), 453-463). Anumber of HCV treatments are reviewed by Bymock et al. in AntiviralChemistry & Chemotherapy, 11:2; 79-95 (2000).

RNA-dependent RNA polymerase (RdRp) is one of the best studied targetsfor the development of novel HCV therapeutic agents. The NS5B polymeraseis a target for inhibitors in early human clinical trials (Sommadossi,J., WO 01/90121 A2, US 2004/0006002 A1). These enzymes have beenextensively characterized at the biochemical and structural level, withscreening assays for identifying selective inhibitors (De Clercq, E.(2001) J. Pharmacol. Exp. Ther. 297:1-10; De Clercq, E. (2001) J. Clin.Virol. 22:73-89). Biochemical targets such as NSSB are important indeveloping HCV therapies since HCV does not replicate in the laboratoryand there are difficulties in developing cell-based assays andpreclinical animal systems.

Currently, there are primarily two antiviral compounds, ribavirin, anucleoside analog, and interferon-alpha (ct) (IFN), which are used forthe treatment of chronic HCV infections in humans. Ribavirin alone isnot effective in reducing viral RNA levels, has significant toxicity,and is known to induce anemia. The combination of IFN and ribavirin hasbeen reported to be effective in the management of chronic hepatitis C(Scott, L. J., et al. Drugs 2002, 62, 507-556) but less than half thepatients given this treatment show a persistent benefit. Other patentapplications disclosing the use of nucleoside analogs to treat hepatitisC virus include WO 01/32153, WO 01/60315, WO 02/057425, WO 02/057287, WO02/032920, WO 02/18404, WO 04/046331, WO2008/089105 and WO2008/141079but additional treatments for HCV infections have not yet becomeavailable for patients. Therefore, drugs having improved antiviral andpharmacokinetic properties with enhanced activity against development ofHCV resistance, improved oral bioavailability, greater efficacy, fewerundesirable side effects and extended effective half-life in vivo (DeFrancesco, R. et al. (2003) Antiviral Research 58:1-16) are urgentlyneeded.

Certain ribosides of the nucleobases pyrrolo[1,2-f][1,2,4]triazine,imidazo[1,5-f][1,2,4]triazine, imidazo[1,2-f][1,2,4]triazine, and[1,2,4]triazolo[4,3-f][1,2,4]triazine have been disclosed inCarbohydrate Research 2001, 331(1), 77-82; Nucleosides & Nucleotides(1996), 15(1-3), 793-807; Tetrahedron Letters (1994), 35(30), 5339-42;Heterocycles (1992), 34(3), 569-74; J. Chem. Soc. Perkin Trans. 1 1985,3, 621-30; J. Chem. Soc. Perkin Trans. 1 1984, 2, 229-38; WO 2000056734;Organic Letters (2001), 3(6), 839-842; J Chem. Soc. Perkin Trans. 11999, 20, 2929-2936; and J. Med. Chem. 1986, 29(11), 2231-5. However,these compounds have not been disclosed as useful for the treatment ofHCV.

Ribosides of pyrrolo[1,2-f][1,2,4]triazinyl,imidazo[1,5-f][1,2,4]triazinyl, imidazo[1,2-f][1,2,4]triazinyl, and[1,2,4]triazolo[4,3-f][1,2,4]triazinyl nucleobases with antiviral,anti-HCV, and anti-RdRp activity have been disclosed by Babu, Y. S.,WO2008/089105 and WO2008/141079; Cho, et al., WO2009/132123 and Francom,et al. WO2010/002877.

Butler, et al., WO2009/132135, has disclosed anti-viralpyrrolo[1,2-f][1,2,4]triazinyl, imidazo[1,5-f][1,2,4]triazinyl,imidazo[1,2-f][1,2,4]triazinyl, and[1,2,4]triazolo[4,3-f][1,2,4]triazinyl nucleosides wherein the 1′position of the nucleoside sugar is substituted with a cyano group.However, the methods described for introducing the 1′ cyano group onlyproduced about a 3:1 ratio of β to α anomers and, in certaincircumstances, the cyanation reactions was particularly slow. Therefore,there is a need to develop more efficient processes and intermediatesfor the syntheses of nucleosides of pyrrolo[1,2-f][1,2,4]triazinyl andimidazo[1,2-f][1,2,4]triazinyl heterocycles.

SUMMARY OF THE INVENTION

Provided are processes and intermediates for the syntheses ofnucleosides of pyrrolo[1,2-f][1,2,4]triazinyl andimidazo[1,2-f][1,2,4]triazinyl heterocycles.

Provided are methods for preparing a compound of Formula I:

or an acceptable salt, thereof;

wherein:

R¹ is H, (C₁-C₈)alkyl, (C₄-C₈)carbocyclylalkyl, (C₁-C₈)substitutedalkyl, (C₂-C₈)alkenyl, (C₂-C₈)substituted alkenyl, (C₂-C₈)alkynyl,(C₂-C₈)substituted alkynyl, or aryl(C₁-C₈)alkyl;

each R^(2a) or R^(2b) is independently H, F or OR⁴;

each R³ is independently (C₁-C₈) alkyl, (C₁-C₈) substituted alkyl,C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀substituted heterocyclyl, C₇-C₂₀ arylalkyl, C₇-C₂₀ substitutedarylalkyl, (C₁-C₈) alkoxy, or (C₁-C₈) substituted alkoxy;

each R⁴ or R⁷ is independently H, optionally substituted allyl,—C(R⁵)₂R⁶, Si(R³)₃, C(O)R⁵, C(O)OR⁵, —(C(R⁵)₂)_(m)—R¹⁵ or

or any two of R⁴ or R⁷ when taken together are —C(R¹⁹)₂—, —C(O)— or—Si(R³)₂(X²)_(m)Si(R³)₂—;

each R¹⁵ is independently —O—C(R⁵)₂R⁶, —Si(R³)₃, C(O)OR⁵, —OC(O)R⁵ or

each R⁵, R¹⁸ or R¹⁹ is independently H, (C₁-C₈) alkyl, (C₁-C₈)substituted alkyl, (C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈)alkynyl, (C₂-C₈) substituted alkynyl, C₆-C₂₀ aryl, C₆-C₂₀ substitutedaryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀ substituted heterocyclyl, C₇-C₂₀arylalkyl or C₇-C₂₀ substituted arylalkyl;

each R⁶ is independently C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, oroptionally substituted heteroaryl;

each R^(a) is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, (C₄-C₈)carbocyclylalkyl, —C(═O)R¹¹,—C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹),—S(O)₂(OR¹¹), or —SO₂NR¹¹R¹²;

X¹ is C—R¹⁰ or N;

each X² is O or CH₂;

each m is 1 or 2;

each n is independently 0, 1 or 2;

each R⁸ is halogen, NR¹¹R¹², N(R¹¹)OR¹¹, NR¹¹NR¹¹R¹², N₃, NO, NO₂, CHO,CH(═NR¹¹), —CH═NHNR¹¹, —CH═N(OR¹¹), —CH(OR¹¹)₂, —C(═O)NR¹¹R¹²,—C(═S)NR¹¹R¹², —C(═O)OR¹¹, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₄-C₈)carbocyclylalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, —C(═O)(C₁-C₈)alkyl, —S(O)_(n)(C₁-C₈)alkyl,aryl(C₁-C₈)alkyl, CN, OR¹¹ or SR₁₁;

each R⁹ or R¹⁰ is independently H, halogen, NR¹¹R¹², N(R¹¹)OR¹¹,N(R¹¹)N(R¹²)(R¹²), N₃, NO, NO₂, CHO, CN, —CH(═NR¹¹), —CH═NNH(R¹¹),—CH═N(OR¹¹), —CH(OR¹¹)₂, —C(═O)NR¹¹R¹², —C(═S)NR¹¹R¹², —C(═O)OR¹¹, R¹¹,OR¹¹ or SR¹¹;

each R¹¹ or R¹² is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, optionallysubstituted aryl, optionally substituted heteroaryl, —C(═O)(C₁-C₈)alkyl,—S(O)_(n)(C₁-C₈)alkyl, aryl(C₁-C₈)alkyl or Si(R³)₃; or R¹¹ and R¹² takentogether with a nitrogen to which they are both attached form a 3 to 7membered heterocyclic ring wherein any one carbon atom of saidheterocyclic ring can optionally be replaced with —O—, —S(O)_(n)— or—NR^(a)—; or R¹¹ and R¹² taken together are —Si(R³)₂(X²)_(m)Si(R³)₂—;

each R²⁰ is independently H, (C₁-C₈)alkyl, substituted (C₁-C₈)alkyl orhalo;

wherein each (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl oraryl(C₁-C₈)alkyl of each R¹, R³, R⁴, R⁵, R⁶, R¹⁸, R¹⁹, R²⁰, R¹¹ or R¹²is, independently, optionally substituted with one or more halo,hydroxy, CN, N₃, N(R^(a))₂ or OR^(a); and wherein one or more of thenon-terminal carbon atoms of each said (C₁-C₈)alkyl is optionallyreplaced with —O—, —S(O)_(n)— or —NR^(a)—;

said method comprising:

(a) providing a compound of Formula II

or an acceptable salt thereof;

wherein R¹⁶ is OH, OR¹⁸, —OC(O)OR¹⁸ or —OC(O)R¹⁸;

(b) treating the compound of Formula II with a cyanide reagent and aLewis acid;

thereby forming the compound of Formula I;

provided that when the compound of Formula II is:

wherein X¹ is CH or N, R¹ is CH₃, R⁸ is NH₂, and R⁹ is NH₂ or H or;

wherein X¹ is CH, R¹ is CH₃, R⁸ is OH, and R⁹ is NH₂ or;

wherein X¹ is CH, each R¹ and R⁹ is H and R⁸ is NH₂;

then said cyanide reagent is not (CH₃)₃SiCN or said Lewis acid is notBF₃—O(CH₂CH₃)₂.

Also provided are compounds of Formula II that are useful intermediatesfor the preparation of compounds of Formula I. Provided are compounds ofFormula II represented by Formula VI:

or an acceptable salt, thereof;

wherein:

R¹ is H, (C₁-C₈)alkyl, (C₄-C₈)carbocyclylalkyl, (C₁-C₈)substitutedalkyl, (C₂-C₈)alkenyl, (C₂-C₈)substituted alkenyl, (C₂-C₈)alkynyl,(C₂-C₈)substituted alkynyl, or aryl(C₁-C₈)alkyl;

each R^(2a) or R^(2b) is independently H, F or OR⁴;

each R³ is independently (C₁-C₈) alkyl, (C₁-C₈) substituted alkyl,C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀substituted heterocyclyl, C₇-C₂₀ arylalkyl, C₇-C₂₀ substitutedarylalkyl, (C₁-C₈) alkoxy, or (C₁-C₈) substituted alkoxy;

each R⁴ or R⁷ is independently H, optionally substituted allyl,—C(R⁵)₂R⁶, Si(R³)₃, C(O)R⁵, C(O)OR⁵, —(C(R⁵)₂)_(m)—R¹⁵ or

or any two of R⁴ or R⁷ when taken together are —C(R¹⁹)₂—, —C(O)— or—Si(R³)₂(X²)_(m)Si(R³)₂—;

each R¹⁵ is independently —O—C(R⁵)₂R⁶, —Si(R³)₃, C(O)OR⁵, —OC(O)R⁵ or

each R⁵, R¹⁸ or R¹⁹ is independently H, (C₁-C₈) alkyl, (C₁-C₈)substituted alkyl, (C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈)alkynyl, (C₂-C₈) substituted alkynyl, C₆-C₂₀ aryl, C₆-C₂₀ substitutedaryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀ substituted heterocyclyl, C₇-C₂₀arylalkyl, or C₇-C₂₀ substituted arylalkyl;

each R⁶ is independently C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, oroptionally substituted heteroaryl;

each R^(a) is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, (C₄-C₈)carbocyclylalkyl, —C(═O)R¹¹,—C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹),—S(O)₂(OR¹¹), or —SO₂NR¹¹R¹²;

X¹ is C—R¹⁰ or N;

each X² is O or CH₂;

each m is 1 or 2;

each n is independently 0, 1 or 2;

each R⁸ is halogen, NR¹¹R¹², N(R¹¹)OR¹¹, NR¹¹NR¹¹R¹², N₃, NO, NO₂, CHO,CH(═NR¹¹), —CH═NHNR¹¹, —CH═N(OR¹), —CH(OR¹¹)₂, —C(═O)NR¹¹R¹²,—C(═S)NR¹¹R¹², —C(═O)OR¹, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₄-C₈)carbocyclylalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, —C(═O)(C₁-C₈)alkyl, —S(O)_(n)(C₁-C₈)alkyl,aryl(C₁-C₈)alkyl, CN, OR¹¹ or SR¹¹;

each R⁹ or R¹⁰ is independently H, halogen, NR¹¹R¹², N(R¹¹)OR,N(R¹¹)N(R¹¹)(R¹²), N₃, NO, NO₂, CHO, CN, —CH(═NR¹¹), —CH═NNH(R¹¹),—CH═N(OR¹¹), —CH(OR¹¹)₂, —C(═O)NR¹¹R¹², —C(═S)NR¹¹R¹², —C(═O)OR¹¹, R¹¹,OR¹¹ or SR¹¹;

each R¹¹ or R¹² is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, optionallysubstituted aryl, optionally substituted heteroaryl, —C(═O)(C₁-C₈)alkyl,—S(O)_(n)(C₁-C₈)alkyl, aryl(C₁-C₈)alkyl or Si(R³)₃; or R¹¹ and R¹² takentogether with a nitrogen to which they are both attached form a 3 to 7membered heterocyclic ring wherein any one carbon atom of saidheterocyclic ring can optionally be replaced with —O—, —S(O)_(n)— or—NR^(a)—; or R¹¹ and R¹² taken together are —Si(R³)₂(X²)_(m)Si(R³)₂—;R¹⁷ is OH, OR¹⁸, —OC(O)OR¹⁸ or —OC(O)R¹⁸;

wherein each (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl oraryl(C₁-C₈)alkyl of each R¹, R³, R⁴, R⁵, R⁶, R¹⁸, R¹⁹, R¹¹ or R¹² is,independently, optionally substituted with one or more halo, hydroxy,CN, N₃, N(R^(a))₂ or OR^(a); and wherein one or more of the non-terminalcarbon atoms of each said (C₁-C₈)alkyl is optionally replaced with —O—,—S(O)_(n)— or —NR^(a)—;

provided that when R¹⁷ is OH or OCH₃, R¹ is H or CH₃ and each R^(2a) andR^(2b) is OR⁴, then each R⁷ and each R⁴ is not H; and

provided that the compound of Formula VI is not a compound of FormulaVII

wherein R¹⁷ is OH and

-   -   (a) X¹ is CH, R¹ is CH₃, R⁸ is NH₂ and R⁹ is NH₂ or H; or    -   (b) X¹ is CH, R¹ is CH₃, R⁸ is OH and R⁹ is NH₂; or    -   (c) X¹ is CH, each R¹ and R⁹ is H and R⁸ is NH₂; or    -   (d) X¹ is N, R¹ is CH₃, R⁸ is NH₂, and R⁹ is H, NH₂ or SCH₃;    -   (e) X¹ is N, R¹ is CH₃, R⁸ is SCH₃ or NHCH₃, and R⁹ is SCH₃; or    -   (f) X¹ is N, R¹ is CH₃, R⁸ is OCH₃, and R⁹ is SCH₃, SO₂CH₃ or        NH₂;

or wherein R¹⁷ is OCH₃, X¹ is CH, each R¹ and R⁹ is H and R⁸ is NH₂.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingdescription, structures and formulas. While the invention will bedescribed in conjunction with the enumerated embodiments, it will beunderstood that they are not intended to limit the invention to thoseembodiments. On the contrary, the invention is intended to cover allalternatives, modifications, and equivalents, which may be includedwithin the scope of the present invention.

In one embodiment, provided is a method of preparing a compound ofFormula I represented by a compound of Formula Ib

or an acceptable salt, thereof,wherein the variables are defined as for Formula I;

said method comprising:

(a) providing a compound of Formula IIb

or an acceptable salt thereof;

wherein the variables are defined as for Formula II;

(b) treating the compound of Formula IIb with a cyanide reagent and aLewis acid;

thereby forming the compound of Formula Ib;

provided that when the compound of Formula IIb is:

wherein X¹ is CH or N, R¹ is CH₃, R⁸ is NH₂, and R⁹ is NH₂ or H or;

wherein X¹ is CH, R¹ is CH₃, R⁸ is OH, and R⁹ is NH₂ or;

wherein X¹ is CH, each R¹ and R⁹ is H and R⁸ is NH₂;

then said cyanide reagent is not (CH₃)₃SiCN or said Lewis acid is notBF₃—O(CH₂CH₃)₂.

In another embodiment of the method of preparing a compound of FormulaIb from a compound of Formula IIb, R¹⁶ of Formula IIb is OH or OR¹⁸. Thefollowing additional independent aspects of this embodiment are asfollows:

(a) R¹ is H. R¹ is CH₃.

(b) X¹ is C—R¹⁰. X¹ is C—H. X¹ is N.

(c) R⁸ is NR¹¹R¹². R⁸ is OR¹¹. R⁸ is SR¹¹

(d) R⁹ is H. R⁹ is NR¹¹R¹². R⁹ is SR¹¹

(e) R^(2b) is OR⁴. R^(2b) is F. Each R^(2a) and R^(2b) is independentlyOR⁴. R^(2a) is OR⁴ and R^(2b) is F. R^(2a) is OR⁴, R^(2b) is F and R⁴ isC(O)R⁵. R^(2a) is OR⁴, R^(2b) is F and R⁴ is C(O)R⁵ wherein R⁵ is phenylor substituted phenyl. R^(2b) is OR⁴ wherein R⁴ is C(R⁵)₂R⁶ and R⁶ isphenyl or substituted phenyl. R^(2b) is OR⁴ wherein R⁴ is CH₂R⁶ and R⁶is phenyl. R^(2b) is OR⁴ wherein R⁴ is CH₂R⁶ and R⁶ is substitutedphenyl. Each R^(2a) and R^(2b) is OH. Each R^(2a) and R^(2b) is OR⁴wherein each R⁴ is independently C(R⁵)₂R⁶ and R⁶ is phenyl orsubstituted phenyl. Each R^(2a) and R^(2b) is OR⁴ wherein each R⁴ isCH₂R⁶ and R⁶ is phenyl. Each R^(2a) and R^(2b) is OR⁴ wherein each R⁴ isCH₂R⁶ and each R⁶ is independently substituted phenyl. Each R^(2a) andR^(2b) is OR⁴ wherein the two R⁴ taken together are —C(R¹⁹)₂—. EachR^(2a) and R^(2b) is OR⁴ wherein the two R⁴ taken together are—C(CH₃)₂—. Each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —CH(R¹⁹)—. Each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴taken together are —CH(R¹⁹)— wherein R¹⁹ is phenyl or substitutedphenyl. R^(2a) is OR⁴ wherein R⁴ is C(R⁵)₂R⁶, R⁶ is phenyl orsubstituted phenyl and R^(2b) is F. R^(2a) is H.

(f) R⁷ is C(O)R⁵. R⁷ is H. R⁷ is C(R⁵)₂R⁶ and R⁶ is phenyl orsubstituted phenyl. R⁷ is CH₂R⁶ and R⁶ is phenyl. R⁷ is CH₂R⁶ and R⁶ issubstituted phenyl. R⁷ is C(R⁵)₂R⁶ and each R⁵ and R⁶ is independentlyphenyl or substituted phenyl. R⁷ is Si(R³)₃. R⁷ is Si(R³)₂(t-butyl)wherein each R³ is CH₃. R⁷ is Si(R³)₂(t-butyl) wherein each R³ isindependently phenyl or substituted phenyl. R⁷ istetrahydro-2H-pyran-2-yl. R⁷ is C(R⁵)₂R⁶ wherein each R⁵ and R⁶ isindependently phenyl or substituted phenyl and each R^(2a) and R^(2b) isOR⁴ wherein the two R⁴ taken together are —C(CH₃)₂—. R⁷ is Si(R³)₃ andeach R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ taken together are—C(CH₃)₂—. R⁷ is Si(R³)₂(t-butyl) wherein each R³ is CH₃ and each R^(2a)and R^(2b) is OR⁴ wherein the two R⁴ taken together are —C(CH₃)₂—. R⁷ isSi(R³)₂(t-butyl) wherein each R³ is independently phenyl or substitutedphenyl and each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —C(CH₃)₂—. R⁷ is tetrahydro-2H-pyran-2-yl and each R^(2a)and R^(2b) is OR⁴ wherein the two R⁴ taken together are —C(CH₃)₂—. R⁷ isC(O)R⁵ and each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —C(CH₃)₂—. R⁷ is C(R⁵)₂R⁶ wherein each R⁵ and R⁶ isindependently phenyl or substituted phenyl and each R^(2a) and R^(2b) isOR⁴ wherein the two R⁴ taken together are —CH(R¹⁹)— wherein R¹⁹ isphenyl or substituted phenyl. R⁷ is Si(R³)₃ and each R^(2a) and R^(2b)is OR⁴ wherein the two R⁴ taken together are —CH(R¹⁹)— wherein R¹⁹ isphenyl or substituted phenyl. R⁷ is Si(R³)₂(t-butyl) wherein each R³ isCH₃ and each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ taken togetherare —CH(R¹⁹)— wherein R¹⁹ is phenyl or substituted phenyl. R⁷ isSi(R³)₂(t-butyl) wherein each R³ is independently phenyl or substitutedphenyl and each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —CH(R¹⁹)— wherein R¹⁹ is phenyl or substituted phenyl. R⁷is tetrahydro-2H-pyran-2-yl and each R^(2a) and R^(2b) is OR⁴ whereinthe two R⁴ taken together are —CH(R¹⁹)— wherein R¹⁹ is phenyl orsubstituted phenyl. R⁷ is C(O)R⁵ and each R^(2a) and R^(2b) is OR⁴wherein the two R⁴ taken together are —CH(R¹⁹)— wherein R¹⁹ is phenyl orsubstituted phenyl. R⁷ is C(O)R⁵ wherein R⁵ is phenyl or substitutedphenyl and R^(2b) is F. R⁷ is H, each R^(2a) and R^(2b) is OR⁴, each R⁴is H and R¹⁶ is OR¹⁸. R⁷ is H, each R^(2a) and R^(2b) is OR⁴, each R⁴ isH and R¹⁶ is OR¹⁸ wherein R¹⁸ is optionally substituted (C₁-C₈) alkyl.

(g) The cyanide reagent is (R³)₃SiCN. The cyanide reagent is (CH₃)₃SiCN.The cyanide reagent is R⁵C(O)CN. The cyanide reagent is R⁵C(O)CN whereinR⁵ is (C₁-C₈) alkoxy or (C₁-C₈) substituted alkoxy.

(h) The Lewis acid comprises boron. The Lewis acid comprises BF₃ orBCl₃. The Lewis acid is BF₃—O(R¹³)₂, BF₃—S(R¹³)₂, BCl₃—O(R¹³)₂ orBCl₃—S(R¹³)₂ wherein each R¹³ is independently (C₁-C₈) alkyl, (C₁-C₈)substituted alkyl, (C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈)alkynyl, (C₂-C₈) substituted alkynyl, C₆-C₂₀ aryl, C₆-C₂₀ substitutedaryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀ substituted heterocyclyl, C₇-C₂₀arylalkyl, or C₇-C₂₀ substituted arylalkyl; wherein each (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl or aryl(C₁-C₈)alkyl of each R¹³ is,independently, optionally substituted with one or more halogens andwherein one or more of the non-terminal carbon atoms of each said(C₁-C₈)alkyl is optionally replaced with —O— or —S(O)_(n)—; or two R¹³when taken together with the oxygen to which they are both attached forma 3 to 7 membered heterocyclic ring wherein one carbon atom of saidheterocyclic ring can optionally be replaced with —O— or —S(O)_(n)—. TheLewis acid is BF₃—O(R¹³)₂ and R¹³ is (C₁-C₈) alkyl. The Lewis acid is(R²⁰)₃CS(O)₂OSi(R³)₃ wherein at least two R²⁰ are halo. The Lewis acidis (R²⁰)₃CS(O)₂OSi(CH₃)₃ wherein at least two R²⁰ are fluorine. TheLewis acid is trimethylsilyltriflate. The Lewis acid is a transitionmetal salt of (R²⁰)₃CS(O)₂OH wherein at least two R²⁰ are halo. TheLewis acid is a transition metal salt of (R²⁰)₃CS(O)₂OH wherein at leasttwo R²⁰ are fluorine. The Lewis acid is a transition metal triflate. TheLewis acid is a lanthanide salt of (R²⁰)₃CS(O)₂OH wherein at least twoR²⁰ are halo. The Lewis acid is a lanthanide salt of (R²⁰)₃CS(O)₂OHwherein at least two R²⁰ are fluorine. The Lewis acid is a lanthanidetriflate. The Lewis acid is an alkaline earth metal salt of(R²⁰)₃CS(O)₂OH wherein at least two R²⁰ are halo. The Lewis acid is analkaline earth metal salt of (R²⁰)₃CS(O)₂OH wherein at least two R²⁰ arefluorine. The Lewis acid is an alkaline earth metal triflate. The Lewisacid is a aluminum, gallium, indium, thallium, tin, lead or bismuth saltof (R²⁰)₃CS(O)₂OH wherein at least two R²⁰ are halo. The Lewis acid is aaluminum, gallium, indium, thallium, tin, lead or bismuth salt of(R²⁰)₃CS(O)₂OH wherein at least two R²⁰ are fluorine. The Lewis acid isa triflate of aluminum, gallium, indium, thallium, tin, lead or bismuth.The Lewis acid comprises a transition metal or salt thereof. The Lewisacid comprises titanium or a salt thereof. The Lewis acid comprisesTiCl₄. The Lewis acid comprises a lanthanide or a salt thereof. TheLewis acid comprises scandium or a salt thereof. The Lewis acidcomprises vanadium or a salt thereof. The Lewis acid comprises tin or asalt thereof. The Lewis acid comprises SnCl₄. The Lewis acid compriseszinc or a salt thereof. The Lewis acid comprises ZnCl₂. The Lewis acidcomprises samarium or a salt thereof. The Lewis acid comprises nickel ora salt thereof. The Lewis acid comprises copper or a salt thereof. TheLewis acid comprises aluminum or a salt thereof. The Lewis acidcomprises gold or a salt thereof.

In another embodiment of a method of preparing a compound of Formula Ib,R¹⁶ of Formula IIb is —OC(O)R¹⁸. The following are additionalindependent aspects of this embodiment:

(a) R¹ is H. R¹ is CH₃.

(b) X¹ is C—R¹⁰. X¹ is C—H. X¹ is N.

(c) R⁸ is NR¹¹R¹². R⁸ is OR¹¹. R⁸ is SR¹¹

(d) R⁹ is H. R⁹ is NR¹¹R¹². R⁹ is SR¹¹

(e) R^(2b) is OR⁴. R^(2b) is F. Each R^(2a) and R^(2b) is independentlyOR⁴. R^(2a) is OR⁴ and R^(2b) is F. R^(2a) is OR⁴, R^(2b) is F and R⁴ isC(O)R⁵. R^(2a) is OR⁴, R^(2b) is F and R⁴ is C(O)R⁵ wherein R⁵ is phenylor substituted phenyl. R^(2b) is OR⁴ wherein R⁴ is C(R⁵)₂R⁶ and R⁶ isphenyl or substituted phenyl. R^(2b) is OR⁴ wherein R⁴ is CH₂R⁶ and R⁶is phenyl. R^(2b) is OR⁴ wherein R⁴ is CH₂R⁶ and R⁶ is substitutedphenyl. Each R^(2a) and R^(2b) is OH. Each R^(2a) and R^(2b) is OR⁴wherein each R⁴ is independently C(R⁵)₂R⁶ and R⁶ is phenyl orsubstituted phenyl. Each R^(2a) and R^(2b) is OR⁴ wherein each R⁴ isCH₂R⁶ and R⁶ is phenyl. Each R^(2a) and R^(2b) is OR⁴ wherein each R⁴ isCH₂R⁶ and each R⁶ is independently substituted phenyl. Each R^(2a) andR^(2b) is OR⁴ wherein the two R⁴ taken together are —C(R¹⁹)₂—. EachR^(2a) and R^(2b) is OR⁴ wherein the two R⁴ taken together are—C(CH₃)₂—. Each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —CH(R¹⁹)—. Each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴taken together are —CH(R¹⁹)— wherein R¹⁹ is phenyl or substitutedphenyl. R^(2a) is OR⁴ wherein R⁴ is C(R⁵)₂R⁶, R⁶ is phenyl orsubstituted phenyl and R^(2b) is F. R^(2a) is H.

(f) R⁷ is C(O)R⁵. R⁷ is H. R⁷ is C(R⁵)₂R⁶ and R⁶ is phenyl orsubstituted phenyl. R⁷ is CH₂R⁶ and R⁶ is phenyl. R⁷ is CH₂R⁶ and R⁶ issubstituted phenyl. R⁷ is C(R⁵)₂R⁶ and each R⁵ and R⁶ is independentlyphenyl or substituted phenyl. R⁷ is Si(R³)₃. R⁷ is Si(R³)₂(t-butyl)wherein each R³ is CH₃. R⁷ is Si(R³)₂(t-butyl) wherein each R³ isindependently phenyl or substituted phenyl. R⁷ istetrahydro-2H-pyran-2-yl. R⁷ is C(R⁵)₂R⁶ wherein each R⁵ and R⁶ isindependently phenyl or substituted phenyl and each R^(2a) and R^(2b) isOR⁴ wherein the two R⁴ taken together are —C(CH₃)₂—. R⁷ is Si(R³)₃ andeach R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ taken together are—C(CH₃)₂—. R⁷ is Si(R³)₂(t-butyl) wherein each R³ is CH₃ and each R^(2a)and R^(2b) is OR⁴ wherein the two R⁴ taken together are —C(CH₃)₂—. R⁷ isSi(R³)₂(t-butyl) wherein each R³ is independently phenyl or substitutedphenyl and each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —C(CH₃)₂—. R⁷ is tetrahydro-2H-pyran-2-yl and each R^(2a)and R^(2b) is OR⁴ wherein the two R⁴ taken together are —C(CH₃)₂—. R⁷ isC(O)R⁵ and each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —C(CH₃)₂—. R⁷ is C(R⁵)₂R⁶ wherein each R⁵ and R⁶ isindependently phenyl or substituted phenyl and each R^(2a) and R^(2b) isOR⁴ wherein the two R⁴ taken together are —CH(R¹⁹)— wherein R¹⁹ isphenyl or substituted phenyl. R⁷ is Si(R³)₃ and each R^(2a) and R^(2b)is OR⁴ wherein the two R⁴ taken together are —CH(R¹⁹)— wherein R¹⁹ isphenyl or substituted phenyl. R⁷ is Si(R³)₂(t-butyl) wherein each R³ isCH₃ and each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ taken togetherare —CH(R¹⁹)— wherein R¹⁹ is phenyl or substituted phenyl. R⁷ isSi(R³)₂(t-butyl) wherein each R³ is independently phenyl or substitutedphenyl and each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —CH(R¹⁹)— wherein R¹⁹ is phenyl or substituted phenyl. R⁷is tetrahydro-2H-pyran-2-yl and each R^(2a) and R^(2b) is OR⁴ whereinthe two R⁴ taken together are —CH(R¹⁹)— wherein R¹⁹ is phenyl orsubstituted phenyl. R⁷ is C(O)R⁵ and each R^(2a) and R^(2b) is OR⁴wherein the two R⁴ taken together are —CH(R¹⁹)— wherein R¹⁹ is phenyl orsubstituted phenyl. R⁷ is C(O)R⁵ wherein R⁵ is phenyl or substitutedphenyl and R^(2b) is F.

(g) The cyanide reagent is (R³)₃SiCN. The cyanide reagent is (CH₃)₃SiCN.The cyanide reagent is R⁵C(O)CN. The cyanide reagent is R⁵C(O)CN whereinR⁵ is (C₁-C₈) alkoxy or (C₁-C₈) substituted alkoxy.

(h) The Lewis acid comprises boron. The Lewis acid comprises BF₃ orBCl₃. The Lewis acid is BF₃—O(R¹³)₂, BF₃—S(R¹³)₂, BCl₃—O(R¹³)₂ orBCl₃—S(R¹³)₂ wherein each R¹³ is independently (C₁-C₈) alkyl, (C₁-C₈)substituted alkyl, (C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈)alkynyl, (C₂-C₈) substituted alkynyl, C₆-C₂₀ aryl, C₆-C₂₀ substitutedaryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀ substituted heterocyclyl, C₇-C₂₀arylalkyl, or C₇-C₂₀ substituted arylalkyl; wherein each (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl or aryl(C₁-C₈)alkyl of each R¹³ is,independently, optionally substituted with one or more halogens andwherein one or more of the non-terminal carbon atoms of each said(C₁-C₈)alkyl is optionally replaced with —O— or —S(O)_(n)—; or two R¹³when taken together with the oxygen to which they are both attached forma 3 to 7 membered heterocyclic ring wherein one carbon atom of saidheterocyclic ring can optionally be replaced with —O— or —S(O)_(n)—. TheLewis acid is BF₃—O(R¹³)₂ and R¹³ is (C₁-C₈) alkyl. The Lewis acid is(R²⁰)₃CS(O)₂OSi(R³)₃ wherein at least two R²⁰ are halo. The Lewis acidis (R²⁰)₃CS(O)₂OSi(CH₃)₃ wherein at least two R²⁰ are fluorine. TheLewis acid is trimethylsilyltriflate. The Lewis acid is a transitionmetal triflate. The Lewis acid is a lanthanide triflate. The Lewis acidis an alkaline metal triflate. The Lewis acid is a triflate of aluminum,gallium, indium, thallium, tin, lead or bismuth. The Lewis acidcomprises a transition metal or salt thereof. The Lewis acid comprisestitanium or a salt thereof. The Lewis acid comprises TiCl₄. The Lewisacid comprises a lanthanide or a salt thereof. The Lewis acid comprisesscandium or a salt thereof. The Lewis acid comprises vanadium or a saltthereof. The Lewis acid comprises tin or a salt thereof. The Lewis acidcomprises SnCl₄. The Lewis acid comprises zinc or a salt thereof. TheLewis acid comprises ZnCl₂. The Lewis acid comprises samarium or a saltthereof. The Lewis acid comprises nickel or a salt thereof. The Lewisacid comprises copper or a salt thereof. The Lewis acid comprisesaluminum or a salt thereof. The Lewis acid comprises gold or a saltthereof.

(i) R¹⁸ is (C₁-C₈)alkyl or substituted (C₁-C₈)alkyl. R¹⁸ is(C₁-C₈)alkyl. R¹⁸ is methyl.

In another embodiment of the method of preparing a compound of FormulaIb, the compound of Formula Ib is represented by Formula Ic

or a salt thereof; and the compound of Formula IIb is represented byFormula IIc

or a salt thereof;

wherein:

R¹⁶ is OH or OR¹⁸;

R¹⁸ is optionally substituted (C₁-C₈) alkyl;

the Lewis acid is (R²⁰)₃CS(O)₂OSi(R³)₃ or a metal salt of(R²⁰)₃CS(O)₂OH;

at least two R²⁰ are halogen; and

said metal is selected from the group consisting aluminum, gallium,indium, thallium, tin, lead, bismuth, an alkaline earth metal, atransition metal and a lanthanide; and

the remaining variables are defined as for Formula IIb. The followingare additional independent aspects of this embodiment:

(a) R¹ is H. R¹ is CH₃.

(b) X¹ is C—R¹⁰. X¹ is C—H. X¹ is N.

(c) R⁸ is NR¹¹R¹². R⁸ is OR¹¹. R⁸ is SR¹¹

(d) R⁹ is H. R⁹ is NR¹¹R¹². R⁹ is SR¹¹.

(e) R^(2b) is OR⁴. R^(2b) is F. R^(2b) is F and R⁴ is C(O)R⁵. R^(2b) isF and R⁴ is C(O)R⁵ wherein R⁵ is phenyl or substituted phenyl. R^(2b) isOR⁴ wherein R⁴ is C(R⁵)₂R⁶ and R⁶ is phenyl or substituted phenyl.R^(2b) is OR⁴ wherein R⁴ is CH₂R⁶ and R⁶ is phenyl. R^(2b) is OR⁴wherein R⁴ is CH₂R⁶ and R⁶ is substituted phenyl. Each OR⁴ and R^(2b) isOH. R^(2b) is OR⁴ wherein each R⁴ is independently C(R⁵)₂R⁶ and R⁶ isphenyl or substituted phenyl. R^(2b) is OR⁴ wherein each R⁴ is CH₂R⁶ andR⁶ is phenyl. R^(2b) is OR⁴ wherein each R⁴ is CH₂R⁶ and each R⁶ isindependently substituted phenyl. R^(2b) is OR⁴ wherein the two R⁴ takentogether are —C(R¹⁹)₂—. R^(2b) is OR⁴ wherein the two R⁴ taken togetherare —C(CH₃)₂—. R^(2b) is OR⁴ wherein the two R⁴ taken together are—CH(R¹⁹)—. R^(2b) is OR⁴ wherein the two R⁴ taken together are —CH(R¹⁹)—wherein R¹⁹ is phenyl or substituted phenyl. R⁴ is C(R⁵)₂R⁶, R⁶ isphenyl or substituted phenyl and R^(2b) is F.

(f) R⁷ is C(O)R⁵. R⁷ is H. R⁷ is C(R⁵)₂R⁶ and R⁶ is phenyl orsubstituted phenyl. R⁷ is CH₂R⁶ and R⁶ is phenyl. R⁷ is CH₂R⁶ and R⁶ issubstituted phenyl. R⁷ is C(R⁵)₂R⁶ and each R⁵ and R⁶ is independentlyphenyl or substituted phenyl. R⁷ is Si(R³)₃. R⁷ is Si(R³)₂(t-butyl)wherein each R³ is CH₃. R⁷ is Si(R³)₂(t-butyl) wherein each R³ isindependently phenyl or substituted phenyl. R⁷ istetrahydro-2H-pyran-2-yl. R⁷ is C(R⁵)₂R⁶ wherein each R⁵ and R⁶ isindependently phenyl or substituted phenyl and R^(2b) is OR⁴ wherein thetwo R⁴ taken together are —C(CH₃)₂—. R⁷ is Si(R³)₃ and R^(2b) is OR⁴wherein the two R⁴ taken together are —C(CH₃)₂—. R⁷ is Si(R³)₂(t-butyl)wherein each R³ is CH₃ and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —C(CH₃)₂—. R⁷ is Si(R³)₂(t-butyl) wherein each R³ isindependently phenyl or substituted phenyl and R^(2b) is OR⁴ wherein thetwo R⁴ taken together are —C(CH₃)₂—. R⁷ is tetrahydro-2H-pyran-2-yl andR^(2b) is OR⁴ wherein the two R⁴ taken together are —C(CH₃)₂—. R⁷ isC(O)R⁵ and R^(2b) is OR⁴ wherein the two R⁴ taken together are—C(CH₃)₂—. R⁷ is C(R⁵)₂R⁶ wherein each R⁵ and R⁶ is independently phenylor substituted phenyl and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —CH(R¹⁹)— wherein R¹⁹ is phenyl or substituted phenyl. R⁷is Si(R³)₃ and R^(2b) is OR⁴ wherein the two R⁴ taken together are—CH(R¹⁹)— wherein R¹⁹ is phenyl or substituted phenyl. R⁷ isSi(R³)₂(t-butyl) wherein each R³ is CH₃ and R^(2b) is OR⁴ wherein thetwo R⁴ taken together are —CH(R¹⁹)— wherein R¹⁹ is phenyl or substitutedphenyl. R⁷ is Si(R³)₂(t-butyl) wherein each R³ is independently phenylor substituted phenyl and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —CH(R¹⁹)— wherein R¹⁹ is phenyl or substituted phenyl. R⁷is tetrahydro-2H-pyran-2-yl and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —CH(R¹⁹)— wherein R¹⁹ is phenyl or substituted phenyl. R⁷is C(O)R⁵ and R^(2b) is OR⁴ wherein the two R⁴ taken together are—CH(R¹⁹)— wherein R¹⁹ is phenyl or substituted phenyl. R⁷ is C(O)R⁵wherein R⁵ is phenyl or substituted phenyl and R^(2b) is F. R⁷ is H,R^(2b) is OR⁴, each R⁴ is H and R¹⁶ is OR¹⁸. R⁷ is H, R^(2b) is OR⁴,each R⁴ is H and R¹⁶ is OR¹⁸ wherein R¹⁸ is optionally substituted(C₁-C₈) alkyl.

(g) The cyanide reagent is (R³)₃SiCN. The cyanide reagent is (CH₃)₃SiCN.The cyanide reagent is R⁵C(O)CN. The cyanide reagent is R⁵C(O)CN whereinR⁵ is (C₁-C₈) alkoxy or (C₁-C₈) substituted alkoxy.

(h) The Lewis acid is (R²⁰)₃CS(O)₂OSi(R³)₃ wherein at least two R²⁰ arehalo. The Lewis acid is (R²⁰)₃CS(O)₂OSi(CH₃)₃ wherein at least two R²⁰are fluorine. The Lewis acid is trimethylsilyltriflate. The Lewis acidis a transition metal salt of (R²⁰)₃CS(O)₂OH wherein at least two R²⁰are halo. The Lewis acid is a transition metal salt of (R²⁰)₃CS(O)₂OHwherein at least two R²⁰ are fluorine. The Lewis acid is a transitionmetal triflate. The Lewis acid is a lanthanide salt of (R²⁰)₃CS(O)₂OHwherein at least two R²⁰ are halo. The Lewis acid is a lanthanide saltof (R²⁰)₃CS(O)₂OH wherein at least two R²⁰ are fluorine. The Lewis acidis a lanthanide triflate. The Lewis acid is an alkaline earth metal saltof (R²⁰)₃CS(O)₂OH wherein at least two R²⁰ are halo. The Lewis acid is aalkaline earth metal salt of (R²⁰)₃CS(O)₂OH wherein at least two R²⁰ arefluorine. The Lewis acid is an alkaline earth metal triflate. The Lewisacid is a aluminum, gallium, indium, thallium, tin, lead or bismuth saltof (R²⁰)₃CS(O)₂OH wherein at least two R²⁰ are halo. The Lewis acid is aaluminum, gallium, indium, thallium, tin, lead or bismuth salt of(R²⁰)₃CS(O)₂OH wherein at least two R²⁰ are fluorine. The Lewis acid isa triflate of aluminum, gallium, indium, thallium, tin, lead or bismuth.The Lewis acid is a triflate of indium.

In another embodiment of the method of preparing a compound of FormulaIc from a compound of Formula IIc, each X¹ is CH and each R⁸ is NR¹¹R¹².In another aspect of this embodiment, each R⁸ is NH₂. In another aspectof this embodiment, each R⁹ is H. In another aspect of this embodiment,each R⁸ is NH₂ and each R⁹ is H. In another aspect of this embodiment,the Lewis acid is (R²⁰)₃CS(O)₂OSi(CH₃)₃ wherein at least two R²⁰ arefluorine. In another aspect of this embodiment, the Lewis acid istrimethylsilyl triflate. In another aspect of this embodiment, the Lewisacid is a transition metal triflate. In another aspect of thisembodiment, the Lewis acid is a lanthanide triflate. In another aspectof this embodiment, the Lewis acid is an alkaline earth metal triflate.In another aspect of this embodiment, the Lewis acid is a triflate ofaluminum, gallium, indium, thallium, tin, lead or bismuth. In anotheraspect of this embodiment, the Lewis acid is a triflate of indium. Inanother aspect of this embodiment, the cyanide reagent is (R³)₃SiCN. Inanother aspect of this embodiment, the cyanide reagent is (CH₃)₃SiCN. Inanother aspect of this embodiment, the Lewis acid is(R²⁰)₃CS(O)₂OSi(CH₃)₃ wherein at least two R²⁰ are fluorine and thecyanide reagent is (R³)₃SiCN. In another aspect of this embodiment, theLewis acid is trimethylsilyl triflate and the cyanide reagent is(R³)₃SiCN. In another aspect of this embodiment, the Lewis acid istrimethylsilyl triflate and the cyanide reagent is (CH₃)₃SiCN. Inanother aspect of this embodiment, R⁷ is C(O)R⁵. In another aspect ofthis embodiment, R⁷ is H. In another aspect of this embodiment, R⁷ isCH₂R⁶ and R⁶ is phenyl or substituted phenyl. In another aspect of thisembodiment, R⁷ is Si(R³)₃. In another aspect of this embodiment, R⁷ istetrahydro-2H-pyran-2-yl. In another aspect of this embodiment, R⁷ isSi(R³)₃ and R^(2b) is OR⁴ wherein the two R⁴ taken together are—C(CH₃)₂—. In another aspect of this embodiment, R⁷ istetrahydro-2H-pyran-2-yl and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —C(CH₃)₂—. In another aspect of this embodiment, R⁷ isC(O)R⁵ and R^(2b) is OR⁴ wherein the two R⁴ taken together are—C(CH₃)₂—. In another aspect of this embodiment, R⁷ is C(O)R⁵ wherein R⁵is phenyl or substituted phenyl and R^(2b) is F. In another aspect ofthis embodiment, R⁷ is H, R^(2b) is OR⁴, each R⁴ is H and R¹⁶ is OR¹⁸.In another aspect of this embodiment, R⁷ is H, R^(2b) is OR⁴, each R⁴ isH and R¹⁶ is OR¹⁸ wherein R¹⁸ is optionally substituted (C₁-C₈) alkyl.

In another embodiment of the method of preparing a compound of FormulaIc from a compound of Formula IIc, each X¹ is CH, each R¹ is H or(C₁-C₈)alkyl, each R⁸ is NH₂ and each R⁹ is H. In another aspect of thisembodiment, the Lewis acid is (R²⁰)₃CS(O)₂OSi(CH₃)₃ wherein at least twoR²⁰ are fluorine. In another aspect of this embodiment, the Lewis acidis trimethylsilyl triflate. In another aspect of this embodiment, theLewis acid is a transition metal triflate. In another aspect of thisembodiment, the Lewis acid is a lanthanide triflate. In another aspectof this embodiment, the Lewis acid is an alkaline earth metal triflate.In another aspect of this embodiment, the Lewis acid is a triflate ofaluminum, gallium, indium, thallium, tin, lead or bismuth. In anotheraspect of this embodiment, the Lewis acid is a triflate of indium. Inanother aspect of this embodiment, the cyanide reagent is (R³)₃SiCN. Inanother aspect of this embodiment, the cyanide reagent is (CH₃)₃SiCN. Inanother aspect of this embodiment, the Lewis acid is(R²⁰)₃CS(O)₂OSi(CH₃)₃ wherein at least two R²⁰ are fluorine and thecyanide reagent is (R³)₃SiCN. In another aspect of this embodiment, theLewis acid is trimethylsilyl triflate and the cyanide reagent is(R³)₃SiCN. In another aspect of this embodiment, the Lewis acid istrimethylsilyl triflate and the cyanide reagent is (CH₃)₃SiCN. Inanother aspect of this embodiment, R⁷ is C(O)R⁵. In another aspect ofthis embodiment, R⁷ is H. In another aspect of this embodiment, R⁷ isCH₂R⁶ and R⁶ is phenyl or substituted phenyl. In another aspect of thisembodiment, R⁷ is Si(R³)₃. In another aspect of this embodiment, R⁷ istetrahydro-2H-pyran-2-yl. In another aspect of this embodiment, R⁷ isSi(R³)₃ and R^(2b) is OR⁴ wherein the two R⁴ taken together are—C(CH₃)₂—. In another aspect of this embodiment, R⁷ istetrahydro-2H-pyran-2-yl and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —C(CH₃)₂—. In another aspect of this embodiment, R⁷ isC(O)R⁵ and R^(2b) is OR⁴ wherein the two R⁴ taken together are—C(CH₃)₂—. In another aspect of this embodiment, R⁷ is C(O)R⁵ wherein R⁵is phenyl or substituted phenyl and R^(2b) is F. In another aspect ofthis embodiment, R⁷ is H, R^(2b) is OR⁴, each R⁴ is H and R¹⁶ is OR¹⁸.In another aspect of this embodiment, R⁷ is H, R^(2b) is OR⁴, each R⁴ isH and R¹⁶ is OR¹⁸ wherein R¹⁸ is optionally substituted (C₁-C₈) alkyl.

Typically, the method of preparing compounds of Formula I, Ib or Ic froma compound of Formula II, IIb or IIc, respectively, are preformed in asuitable aprotic solvent at about −78 to 80° C. for about 10 minutesabout 3 days. Non-limiting examples of suitable aprotic solvents includeCH₂Cl₂, acetonitrile, CH₂ClCH₂C₁ or other halocarbon solvents. Moretypically, the method is performed at about −20 to about 65° C. forabout 10 minutes to 4 hours. The mole ratio of the compound of FormulaII, IIb or IIc to cyanide reagent is about 1:1 to 1:10, more typicallyabout 1:2 to 1:6. The mole ratio of the compound of Formula II, IIb orIIc to Lewis acid is about 1:0.1 to about 1:10, more typically about1:0.7 to about 1:6.

The conversion of the compounds of Formula II, IIb or IIc to a compoundof Formula I, Ib or Ic, respectively, is promoted by Lewis acids. ManyLewis acids may promote this conversion including many that arecommercially available. Non-limiting examples of Lewis acids comprisingboron that are suitable for promoting this conversion are borontrifluoride etherates of methyl, ethyl, propyl, and butyl ethers; borontrifluoride-tert-butyl methyl etherate; boron trifluoride and borontrifluoride methyl sulfide complex. Non-limiting examples of Lewis acidscomprising trialkylsilyl groups that are suitable for promoting thisconversion are tri-(C₁-C₁₂alkyl)silyl-polyfluoro(C₁-C₁₂)alkylsulfonates, trimethylsilylpolyfluoro(C₁-C₁₂)alkylsulfonates, trimethylsilyltrifluoromethanesulfonate, tert-butyldimethylsilyltrifluoromethanesulfonate and triethylsilyl trifluoromethanesulfonate.Additional non-limiting examples of Lewis acids suitable for promotingthis conversion are transition metal polyfluoro(C₁-C₁₂)alkylsulfonates,lanthanide polyfluoro(C₁-C₁₂)alkylsulfonates, alkaline earth metalpolyfluoro(C₁-C₁₂)alkylsulfonates, polyfluoro(C₁-C₁₂)alkylsulfonates ofaluminium, gallium, indium, thallium, tin, lead and bismuth, TiCl₄,AlCl₃, ZnCl₂, ZnI₂, SnCl₄, InCl₃, Sc(trifluoromethanesulfonate)₃,Sn(trifluoromethanesulfonate)₂, InBr₃, indium(trifluoromethanesulfonate)₃, AuCl₃, montmorilite clays,Cu(trifluoromethanesulfonate)₂, vanadyl trifluoromethanesulfonate, andsalen complexes of Ti and Vn (Belokon, et al., Tetrahedron 2001, 771).In a preferred embodiment, the Lewis acid is trimethylsilyltrifluoromethanesulfonate. In another preferred embodiment, the Lewisacid is trimethylsilyl trifluoromethanesulfonate and the yield of thecompound of Formula I, Ib or Ic is about 50% or greater. In anotherpreferred embodiment, the Lewis acid is trimethylsilyltrifluoromethanesulfonate and the yield of the compound of Formula I, Ibor Ic is about 70% or greater. In another preferred embodiment, theLewis acid is trimethylsilyl trifluoromethanesulfonate and the yield ofthe compound of Formula I, Ib or Ic is about 90% or greater. In anotherpreferred embodiment, the Lewis acid is trimethylsilyltrifluoromethanesulfonate and the ratio of β to α anomer of the compoundof formula I, Ib, or Ic is about 3.5 to 1 or greater. In anotherpreferred embodiment, the Lewis acid is trimethylsilyltrifluoromethanesulfonate and the ratio of β to α anomer of the compoundof Formula I, Ib, or Ic is about 4 to 1 or greater. In another preferredembodiment, the Lewis acid is trimethylsilyl trifluoromethanesulfonateand the ratio of β to α anomer of the compound of formula I, Ib, or Icis about 5 to 1 or greater. In another preferred embodiment, the Lewisacid is trimethylsilyl trifluoromethanesulfonate and the ratio of β to αanomer of the compound of formula I, Ib, or Ic is about 6 to 1 orgreater. In another preferred embodiment, the Lewis acid istrimethylsilyl trifluoromethanesulfonate and the ratio of β to α anomerof the compound of formula I, Ib, or Ic is about 8 to 1 or greater. Inanother preferred embodiment, the Lewis acid is trimethylsilyltrifluoromethanesulfonate and the ratio of β to α anomer of the compoundof formula I, Ib, or Ic is about 10 to 1 or greater.

In another embodiment, provided is a method of preparing a compound ofFormula II or IIb wherein R¹⁶ is —OC(O)R¹⁸,

the method comprising:

(c) providing a compound of Formula II or IIb wherein R¹⁶ is OH; and

(d) treating the compound of Formula II or IIb wherein R¹⁶ is OH withYC(O)R¹⁸ wherein Y is selected from halogen, cyano, imidazol-1-yl;pyrazol-1-yl, —O—C(O)R¹⁸ or —O—C(O)OR¹⁸;

thereby forming a compound of Formula II or IIb wherein R¹⁶ is—OC(O)R¹⁸.

In another embodiment, the method of preparing the compound of FormulaII or IIb wherein R¹⁶ is OC(O)R¹⁸ has the following additionalindependent aspects.

(a) R¹ is H. R¹ is CH₃.

(b) X¹ is C—R¹⁰. X¹ is C—H. X¹ is N.

(c) R⁸ is NR¹¹R¹². R⁸ is OR¹¹. R⁸ is SR¹¹

(d) R⁹ is H. R⁹ is NR¹¹R¹². R⁹ is SR¹¹

(e) R^(2b) is OR⁴. R^(2b) is F. Each R^(2a) and R^(2b) is independentlyOR⁴. R^(2a) is OR⁴ and R^(2b) is F. R^(2a) is OR⁴, R^(2b) is F and R⁴ isC(O)R⁵. R^(2a) is OR⁴, R^(2b) is F and R⁴ is C(O)R⁵ wherein R⁵ is phenylor substituted phenyl. R^(2b) is OR⁴ wherein R⁴ is C(R⁵)₂R⁶ and R⁶ isphenyl or substituted phenyl. R^(2b) is OR⁴ wherein R⁴ is CH₂R⁶ and R⁶is phenyl. R^(2b) is OR⁴ wherein R⁴ is CH₂R⁶ and R⁶ is substitutedphenyl. Each R^(2a) and R^(2b) is OR⁴ wherein each R⁴ is independentlyC(R⁵)₂R⁶ and R⁶ is phenyl or substituted phenyl. Each R^(2a) and R^(2b)is OR⁴ wherein each R⁴ is CH₂R⁶ and R⁶ is phenyl. Each R^(2a) and R^(2b)is OR⁴ wherein each R⁴ is CH₂R⁶ and each R⁶ is independently substitutedphenyl. Each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ taken togetherare —C(R¹⁹)₂—. Each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —C(CH₃)₂—. Each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴taken together are —CH(R¹⁹)—. Each R^(2a) and R^(2b) is OR⁴ wherein thetwo R⁴ taken together are —CH(R¹⁹)— wherein R¹⁹ is phenyl or substitutedphenyl. R^(2a) is OR⁴ wherein R⁴ is C(R⁵)₂R⁶, R⁶ is phenyl orsubstituted phenyl and R^(2b) is F. R^(2a) is H.

(f) R⁷ is C(O)R⁵. R⁷ is C(R⁵)₂R⁶ and R⁶ is phenyl or substituted phenyl.R⁷ is CH₂R⁶ and R⁶ is phenyl. R⁷ is CH₂R⁶ and R⁶ is substituted phenyl.R⁷ is C(R⁵)₂R⁶ and each R⁵ and R⁶ is independently phenyl or substitutedphenyl. R⁷ is Si(R³)₃. R⁷ is Si(R³)₂(t-butyl) wherein each R³ is CH₃. R⁷is Si(R³)₂(t-butyl) wherein each R³ is independently phenyl orsubstituted phenyl. R⁷ is tetrahydro-2H-pyran-2-yl. R⁷ is C(R⁵)₂R⁶wherein each R⁵ and R⁶ is independently phenyl or substituted phenyl andeach R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ taken together are—C(CH₃)₂—. R⁷ is Si(R³)₃ and each R^(2a) and R^(2b) is OR⁴ wherein thetwo R⁴ taken together are —C(CH₃)₂—. R⁷ is Si(R³)₂(t-butyl) wherein eachR³ is CH₃ and each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —C(CH₃)₂—. R⁷ is Si(R³)₂(t-butyl) wherein each R³ isindependently phenyl or substituted phenyl and each R^(2a) and R^(2b) isOR⁴ wherein the two R⁴ taken together are —C(CH₃)₂—. R⁷ istetrahydro-2H-pyran-2-yl and each R^(2a) and R^(2b) is OR⁴ wherein thetwo R⁴ taken together are —C(CH₃)₂—. R⁷ is C(O)R⁵ and each R^(2a) andR^(2b) is OR⁴ wherein the two R⁴ taken together are —C(CH₃)₂—. R⁷ isC(R⁵)₂R⁶ wherein each R⁵ and R⁶ is independently phenyl or substitutedphenyl and each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —CH(R¹⁹)— wherein R¹⁹ is phenyl or substituted phenyl. R⁷is Si(R³)₃ and each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —CH(R¹⁹)— wherein R¹⁹ is phenyl or substituted phenyl. R⁷is Si(R³)₂(t-butyl) wherein each R³ is CH₃ and each R^(2a) and R^(2b) isOR⁴ wherein the two R⁴ taken together are —CH(R¹⁹)— wherein R¹⁹ isphenyl or substituted phenyl. R⁷ is Si(R³)₂(t-butyl) wherein each R³ isindependently phenyl or substituted phenyl and each R^(2a) and R^(2b) isOR⁴ wherein the two R⁴ taken together are —CH(R¹⁹)— wherein R¹⁹ isphenyl or substituted phenyl. R⁷ is tetrahydro-2H-pyran-2-yl and eachR^(2a) and R^(2b) is OR⁴ wherein the two R⁴ taken together are —CH(R¹⁹)—wherein R¹⁹ is phenyl or substituted phenyl. R⁷ is C(O)R⁵ and eachR^(2a) and R^(2b) is OR⁴ wherein the two R⁴ taken together are —CH(R¹⁹)—wherein R¹⁹ is phenyl or substituted phenyl. R⁷ is C(O)R⁵ wherein R⁵ isphenyl or substituted phenyl and R^(2b) is F.

(g) R¹⁸ is (C₁-C₈)alkyl or substituted (C₁-C₈)alkyl. R¹⁸ is(C₁-C₈)alkyl. R¹⁸ is methyl.

In one embodiment, the mole ratio of the compound of Formula II, IIb orIIc wherein R¹⁶ is OH to YC(O)R¹⁸ is about 1:1 to about 1:10, preferablyabout 1:1 to about 1:6.5. Typically, the compound of Formula II, IIb orIIc wherein R¹⁶ is OH is treated with YC(O)R¹⁸ in an aprotic solventsuch as, but not limited to, pyridine, THF or ether at about −30 toabout 125° C. for about 30 minutes to about 24 hours. In one embodiment,Y is halogen. In another embodiment, Y is Cl. In another embodiment, Yis cyano. In another embodiment, Y is imidazol-1-yl. In anotherembodiment, Y is pyrazol-1-yl. In another embodiment, Y is —O—C(O)R¹⁸.In another embodiment, Y is —O—C(O)OR¹⁸. In a particular embodiment, R¹⁸is C₁-C₆ alkyl. In another particular embodiment, R¹⁸ is CH₃. In anotherembodiment, R¹⁸ is C₁-C₆ alkyl and Y is —O—C(O)R¹⁸. In anotherembodiment, R¹⁸ is CH₃ and Y—O—C(O)R¹⁸.

The reaction of the compound of Formula II, IIb or IIc wherein R¹⁶ is OHwith YC(O)R¹⁸ may be catalyzed or accelerated in the presence of asuitable base. Non-limiting examples of suitable bases includetriethylamine, di-isopropylethylamine, pyridine,4-dimethylaminopyridine, DBU, NaH and KH. The mole ratio of YC(O)R¹⁸ tobase is typically about 1:1 to 1:4.

In another embodiment, provided is a method of preparing a compound ofFormula II wherein R¹⁶ is OH,

the method comprising:

(e) providing a compound of Formula III:

(f) treating the compound of Formula III with an organometallic compoundof Formula IV:

wherein M is MgX³ or Li and X³ is halogen;

thereby forming a compound of Formula II wherein R¹⁶ is OH;

provided that when M is Li, the compound of Formula II is not a compoundof Formula VII

wherein R¹⁷ is OH; and

-   -   (a) X¹ is CH, R¹ is CH₃, R⁸ is NH₂ and R⁹ is NH₂ or H; or    -   (b) X¹ is CH, R¹ is CH₃, R⁸ is OH and R⁹ is NH₂; or    -   (c) X¹ is CH, each R¹ and R⁹ is H and R⁸ is NH₂; or    -   (d) X¹ is N, R¹ is CH₃, R⁸ is NH₂, and R⁹ is H, NH₂ or SCH₃; or    -   (e) X¹ is N, R¹ is CH₃, R⁸ is SCH₃ or NHCH₃, and R⁹ is SCH₃; or    -   (f) X¹ is N, R¹ is CH₃, R⁸ is OCH₃, and R⁹ is SCH₃, SO₂CH₃ or        NH₂.

In another embodiment of the method of preparing a compound of FormulaII wherein R¹⁶ is OH, the compound of Formula II is Formula IIb whereinR¹⁶ is OH and the compound of Formula III is a compound of Formula IIIb:

provided that when M is Li, the compound of Formula IIb is not acompound of Formula VII

wherein R¹⁷ is OH; and

-   -   (a) X¹ is CH, R¹ is CH₃, R⁸ is NH₂ and R⁹ is NH₂ or H; or    -   (b) X¹ is CH, R¹ is CH₃, R⁸ is OH and R⁹ is NH₂; or    -   (c) X¹ is CH, each R¹ and R⁹ is H and R⁸ is NH₂; or    -   (d) X¹ is N, R¹ is CH₃, R⁸ is NH₂, and R⁹ is H, NH₂ or SCH₃; or    -   (e) X¹ is N, R¹ is CH₃, R⁸ is SCH₃ or NHCH₃, and R⁹ is SCH₃; or    -   (f) X¹ is N, R¹ is CH₃, R⁸ is OCH₃, and R⁹ is SCH₃, SO₂CH₃ or        NH₂.        The following are additional independent aspects of this        embodiment:

(a) R¹ is H. R¹ is CH₃.

(b) R^(2b) is OR⁴. R^(2b) is F. Each R^(2a) and R^(2b) is independentlyOR⁴. R^(2a) is OR⁴ and R^(2b) is F. R^(2a) is OR⁴, R^(2b) is F and R⁴ isC(O)R⁵. R^(2a) is OR⁴, R^(2b) is F and R⁴ is C(O)R⁵ wherein R⁵ is phenylor substituted phenyl. R^(2b) is OR⁴ wherein R⁴ is C(R⁵)₂R⁶ and R⁶ isphenyl or substituted phenyl. R^(2b) is OR⁴ wherein R⁴ is CH₂R⁶ and R⁶is phenyl. R^(2b) is OR⁴ wherein R⁴ is CH₂R⁶ and R⁶ is substitutedphenyl. Each R^(2a) and R^(2b) is OH. Each R^(2a) and R^(2b) is OR⁴wherein each R⁴ is independently C(R⁵)₂R⁶ and R⁶ is phenyl orsubstituted phenyl. Each R^(2a) and R^(2b) is OR⁴ wherein each R⁴ isCH₂R⁶ and R⁶ is phenyl. Each R^(2a) and R^(2b) is OR⁴ wherein each R⁴ isCH₂R⁶ and each R⁶ is independently substituted phenyl. Each R^(2a) andR^(2b) is OR⁴ wherein the two R⁴ taken together are —C(R¹⁹)₂—. EachR^(2a) and R^(2b) is OR⁴ wherein the two R⁴ taken together are—C(CH₃)₂—. Each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —CH(R¹⁹)—. Each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴taken together are —CH(R¹⁹)— wherein R¹⁹ is phenyl or substitutedphenyl. R^(2a) is OR⁴ wherein R⁴ is C(R⁵)₂R⁶, R⁶ is phenyl orsubstituted phenyl and R^(2b) is F. R^(2a) is H.

(c) R⁷ is C(O)R⁵. R⁷ is H. R⁷ is C(R⁵)₂R⁶ and R⁶ is phenyl orsubstituted phenyl. R⁷ is CH₂R⁶ and R⁶ is phenyl. R⁷ is CH₂R⁶ and R⁶ issubstituted phenyl. R⁷ is C(R⁵)₂R⁶ and each R⁵ and R⁶ is independentlyphenyl or substituted phenyl. R⁷ is Si(R³)₃. R⁷ is Si(R³)₂(t-butyl)wherein each R³ is CH₃. R⁷ is Si(R³)₂(t-butyl) wherein each R³ isindependently phenyl or substituted phenyl. R⁷ istetrahydro-2H-pyran-2-yl. R⁷ is C(R⁵)₂R⁶ wherein each R⁵ and R⁶ isindependently phenyl or substituted phenyl and each R^(2a) and R^(2b) isOR⁴ wherein the two R⁴ taken together are —C(CH₃)₂—. R⁷ is Si(R³)₃ andeach R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ taken together are—C(CH₃)₂—. R⁷ is Si(R³)₂(t-butyl) wherein each R³ is CH₃ and each R^(2a)and R^(2b) is OR⁴ wherein the two R⁴ taken together are —C(CH₃)₂—. R⁷ isSi(R³)₂(t-butyl) wherein each R³ is independently phenyl or substitutedphenyl and each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —C(CH₃)₂—. R⁷ is tetrahydro-2H-pyran-2-yl and each R^(2a)and R^(2b) is OR⁴ wherein the two R⁴ taken together are —C(CH₃)₂—. R⁷ isC(O)R⁵ and each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —C(CH₃)₂—. R⁷ is C(R⁵)₂R⁶ wherein each R⁵ and R⁶ isindependently phenyl or substituted phenyl and each R^(2a) and R^(2b) isOR⁴ wherein the two R⁴ taken together are —CH(R¹⁹)— wherein R¹⁹ isphenyl or substituted phenyl. R⁷ is Si(R³)₃ and each R^(2a) and R^(2b)is OR⁴ wherein the two R⁴ taken together are —CH(R¹⁹)— wherein R¹⁹ isphenyl or substituted phenyl. R⁷ is Si(R³)₂(t-butyl) wherein each R³ isCH₃ and each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ taken togetherare —CH(R¹⁹)— wherein R¹⁹ is phenyl or substituted phenyl. R⁷ isSi(R³)₂(t-butyl) wherein each R³ is independently phenyl or substitutedphenyl and each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —CH(R¹⁹)— wherein R¹⁹ is phenyl or substituted phenyl. R⁷is tetrahydro-2H-pyran-2-yl and each R^(2a) and R^(2b) is OR⁴ whereinthe two R⁴ taken together are —CH(R¹⁹)— wherein R¹⁹ is phenyl orsubstituted phenyl. R⁷ is C(O)R⁵ and each R^(2a) and R^(2b) is OR⁴wherein the two R⁴ taken together are —CH(R¹⁹)— wherein R¹⁹ is phenyl orsubstituted phenyl. R⁷ is C(O)R⁵ wherein R⁵ is phenyl or substitutedphenyl and R^(2b) is F.

(d) X¹ is C—R¹⁰. X¹ is C—H. X¹ is N.

(e) R⁸ is NR¹¹R¹². R⁸ is OR¹¹. R⁸ is SR¹.

(f) R⁹ is H. R⁹ is NR¹¹R¹². R⁹ is SR¹¹.

(g) Each R¹¹ or R¹² is independently (C₁-C₈)alkyl, —C(═O)(C₁-C₈)alkyl,—S(O)_(n)(C₁-C₈)alkyl, aryl(C₁-C₈)alkyl or Si(R³)₃; or R¹¹ and R¹² takentogether with a nitrogen to which they are both attached form a 3 to 7membered heterocyclic ring; or R¹¹ and R¹² taken together are—Si(R³)₂(X²)_(m)Si(R³)₂—. Each R¹¹ or R¹² is independently (C₁-C₈)alkyl.Each R¹¹ or R¹² is independently Si(R³)₃. Each R¹¹ or R¹² isindependently Si(R³)₃ wherein at least two of R³ are CH₃ or phenyl. EachR¹¹ or R¹² is independently Si(CH₃)₃. Each R¹¹ and R¹² of NR¹¹R¹² isindependently selected from Si(R³)₃ or R¹¹ and R¹² of NR¹¹R¹² takentogether are —Si(R³)₂(X²)_(m)Si(R³)₂—. Each R¹¹ and R¹² of NR¹¹R¹² isindependently selected from Si(R³)₃ or R¹¹ and R¹² of NR¹¹R¹² takentogether are —Si(R³)₂(X²)_(m)Si(R³)₂—; and each R³ is methyl.

(h) M is MgX³. M is Li.

In another embodiment of the method of preparing a compound of FormulaIIb wherein R¹⁶ is OH, the compound of Formula IIb is Formula IIc andthe compound of Formula IIIb is a compound of Formula IIIc:

provided that when M is Li, the compound of Formula IIc is not acompound of Formula VII

wherein R¹⁷ is OH; and

-   -   (a) X¹ is CH, R¹ is CH₃, R⁸ is NH₂ and R⁹ is NH₂ or H; or    -   (b) X¹ is CH, R¹ is CH₃, R⁸ is OH and R⁹ is NH₂; or    -   (c) X¹ is CH, each R¹ and R⁹ is H and R⁸ is NH₂; or    -   (d) X¹ is N, R¹ is CH₃, R⁸ is NH₂, and R⁹ is H, NH₂ or SCH₃; or    -   (e) X¹ is N, R¹ is CH₃, R⁸ is SCH₃ or NHCH₃, and R⁹ is SCH₃; or    -   (f) X¹ is N, R¹ is CH₃, R⁸ is OCH₃, and R⁹ is SCH₃, SO₂CH₃ or        NH₂.        The following are additional independent aspects of this        embodiment:

(a) R¹ is H. R¹ is CH₃.

(b) R^(2b) is OR⁴. R^(2b) is F. R^(2b) is F and R⁴ is C(O)R⁵. R^(2b) isF and R⁴ is C(O)R⁵ wherein R⁵ is phenyl or substituted phenyl. R^(2b) isOR⁴ wherein R⁴ is C(R⁵)₂R⁶ and R⁶ is phenyl or substituted phenyl.R^(2b) is OR⁴ wherein R⁴ is CH₂R⁶ and R⁶ is phenyl. R^(2b) is OR⁴wherein R⁴ is CH₂R⁶ and R⁶ is substituted phenyl. Each OR⁴ and R^(2b) isOH. R^(2b) is OR⁴ wherein each R⁴ is independently C(R⁵)₂R⁶ and R⁶ isphenyl or substituted phenyl. R^(2b) is OR⁴ wherein each R⁴ is CH₂R⁶ andR⁶ is phenyl. R^(2b) is OR⁴ wherein each R⁴ is CH₂R⁶ and each R⁶ isindependently substituted phenyl. R^(2b) is OR⁴ wherein the two R⁴ takentogether are —C(R¹⁹)₂—. R^(2b) is OR⁴ wherein the two R⁴ taken togetherare —C(CH₃)₂—. R^(2b) is OR⁴ wherein the two R⁴ taken together are—CH(R¹⁹)—. R^(2b) is OR⁴ wherein the two R⁴ taken together are —CH(R¹⁹)—wherein R¹⁹ is phenyl or substituted phenyl. R⁴ is C(R⁵)₂R⁶, R⁶ isphenyl or substituted phenyl and R^(2b) is F.

(c) R⁷ is C(O)R⁵. R⁷ is H. R⁷ is C(R⁵)₂R⁶ and R⁶ is phenyl orsubstituted phenyl. R⁷ is CH₂R⁶ and R⁶ is phenyl. R⁷ is CH₂R⁶ and R⁶ issubstituted phenyl. R⁷ is C(R⁵)₂R⁶ and each R⁵ and R⁶ is independentlyphenyl or substituted phenyl. R⁷ is Si(R³)₃. R⁷ is Si(R³)₂(t-butyl)wherein each R³ is CH₃. R⁷ is Si(R³)₂(t-butyl) wherein each R³ isindependently phenyl or substituted phenyl. R⁷ istetrahydro-2H-pyran-2-yl. R⁷ is C(R⁵)₂R⁶ wherein each R⁵ and R⁶ isindependently phenyl or substituted phenyl and R^(2b) is OR⁴ wherein thetwo R⁴ taken together are —C(CH₃)₂—. R⁷ is Si(R³)₃ and R^(2b) is OR⁴wherein the two R⁴ taken together are —C(CH₃)₂—. R⁷ is Si(R³)₂(t-butyl)wherein each R³ is CH₃ and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —C(CH₃)₂—. R⁷ is Si(R³)₂(t-butyl) wherein each R³ isindependently phenyl or substituted phenyl and R^(2b) is OR⁴ wherein thetwo R⁴ taken together are —C(CH₃)₂—. R⁷ is tetrahydro-2H-pyran-2-yl andR^(2b) is OR⁴ wherein the two R⁴ taken together are —C(CH₃)₂—. R⁷ isC(O)R⁵ and R^(2b) is OR⁴ wherein the two R⁴ taken together are—C(CH₃)₂—. R⁷ is C(R⁵)₂R⁶ wherein each R⁵ and R⁶ is independently phenylor substituted phenyl and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —CH(R¹⁹)— wherein R¹⁹ is phenyl or substituted phenyl. R⁷is Si(R³)₃ and R^(2b) is OR⁴ wherein the two R⁴ taken together are—CH(R¹⁹)— wherein R¹⁹ is phenyl or substituted phenyl. R⁷ isSi(R³)₂(t-butyl) wherein each R³ is CH₃ and R^(2b) is OR⁴ wherein thetwo R⁴ taken together are —CH(R¹⁹)— wherein R¹⁹ is phenyl or substitutedphenyl. R⁷ is Si(R³)₂(t-butyl) wherein each R³ is independently phenylor substituted phenyl and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —CH(R¹⁹)— wherein R¹⁹ is phenyl or substituted phenyl. R⁷is tetrahydro-2H-pyran-2-yl and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —CH(R¹⁹)— wherein R¹⁹ is phenyl or substituted phenyl. R⁷is C(O)R⁵ and R^(2b) is OR⁴ wherein the two R⁴ taken together are—CH(R¹⁹)— wherein R¹⁹ is phenyl or substituted phenyl. R⁷ is C(O)R⁵wherein R⁵ is phenyl or substituted phenyl and R^(2b) is F.

(d) X¹ is C—R¹⁰. X¹ is C—H. X¹ is N.

(e) R⁸ is NR¹¹R¹². R⁸ is OR¹¹. R⁸ is SR¹¹

(f) R⁹ is H. R⁹ is NR¹¹R¹². R⁹ is SR¹¹

(g) Each R¹¹ or R¹² is independently (C₁-C₈)alkyl, —C(═O)(C₁-C₈)alkyl,—S(O)_(n)(C₁-C₈)alkyl, aryl(C₁-C₈)alkyl or Si(R³)₃; or R¹¹ and R¹² takentogether with a nitrogen to which they are both attached form a 3 to 7membered heterocyclic ring; or R¹¹ and R¹² taken together are—Si(R³)₂(X²)_(m)Si(R³)₂—. Each R¹¹ or R¹² is independently (C₁-C₈)alkyl.Each R¹¹ or R¹² is independently Si(R³)₃. Each R¹¹ or R¹² isindependently Si(R³)₃ wherein at least two of R³ are CH₃ or phenyl. EachR¹ or R¹² is independently Si(CH₃)₃. Each R¹ and R¹² of NR¹¹R¹² isindependently selected from Si(R³)₃ or R¹¹ and R¹² of NR¹¹R¹² takentogether are —Si(R³)₂(X²)_(m)Si(R³)₂—. Each R¹¹ and R¹² of NR¹¹R¹² isindependently selected from Si(R³)₃ or R¹¹ and R¹² of NR¹¹R¹² takentogether are —Si(R³)₂(X²)_(m)Si(R³)₂—; and each R³ is methyl.

(h) M is MgX³. M is Li.

In another embodiment, the method of preparing a compound of Formula Ifurther comprises the method of preparing a compound of Formula IIwherein R¹⁶ is OH.

In another embodiment, the method of preparing a compound of Formula Ibfurther comprises a method for preparing the compound of Formula IIbwherein R¹⁶ is OH.

In another embodiment, the method of preparing a compound of Formula Icfurther comprises the method for preparing a compound of Formula IIcwherein R¹⁶ is OH.

Typically, the method of preparing a compound of Formula II, IIb or IIcwherein R¹⁶ is OH from a compound of Formula III, IIIb or IIIc,respectively, is performed in a suitable aprotic solvent at about −100to about to abut 50 OC for about 5 minutes to 24 hours. Non-limitingexamples of suitable aprotic solvents include THF, dioxane and ether.More typically, the suitable solvent is THF and the preferredtemperature is about −78 to 0° C. The mole ratio of the compound ofFormula IV to the compound of Formula III, IIIb or IIIc is about 1:2 to2:1; preferably about 1:1.

In another embodiment, the method of preparing a compound of Formula II,IIb or IIc wherein R¹⁶ is OH from a compound of Formula III, IIIb orIIIc, respectively, further comprises a method of preparing a compoundof Formula IV wherein M is MgX³ or Li and X³ is halogen, the methodcomprising:

-   -   (g) providing a compound of Formula V:

wherein X³ is Cl, Br or I and

(h) treating the compound of Formula V with an organometallic reagentcomprising an organomagnesium or organolithium compound;

thereby forming a compound of Formula IV.

In another embodiment, the method of preparing a compound of Formula IVfrom a compound of Formula V comprises the following independentaspects:

-   -   (a) X¹ is C—R¹⁰. X¹ is C—H. X¹ is N.    -   (b) R⁸ is NR¹¹R¹². R⁸ is OR¹¹. R⁸ is SR¹¹    -   (c) R⁹ is H. R⁹ is NR¹¹R¹². R⁹ is SR¹¹    -   (d) Each R¹¹ or R¹² is independently (C₁-C₈)alkyl,        —C(═O)(C₁-C₈)alkyl, —S(O)_(n)(C₁-C₈)alkyl, aryl(C₁-C₈)alkyl or        Si(R³)₃; or R¹¹ and R¹² taken together with a nitrogen to which        they are both attached form a 3 to 7 membered heterocyclic ring;        or R¹¹ and R¹² taken together are —Si(R³)₂(X²)_(m)Si(R³)₂—. Each        R¹¹ or R¹² is independently (C₁-C₈)alkyl. Each R¹¹ or R¹² is        independently Si(R³)₃. Each R¹¹ or R¹² is independently Si(R³)₃        wherein at least two of R³ are CH₃ or phenyl. Each R¹¹ or R¹² is        independently Si(CH₃)₃. Each R¹¹ and R¹² of NR¹¹R¹² is        independently selected from Si(R³)₃ or R¹¹ and R¹² of NR¹¹R¹²        taken together are —Si(R³)₂(X²)_(m)Si(R³)₂—. Each R¹¹ and R¹² of        NR¹¹R¹² is independently selected from Si(R³)₃ or R¹¹ and R¹² of        NR¹¹R¹² taken together are —Si(R³)₂(X²)_(m)Si(R³)₂—; and each R³        is methyl.    -   (e) X³ is C₁. X³ is Br. X³ is I.

In one embodiment, the method of preparing a compound of Formula IVcomprises treating a compound of Formula V with a organomagnesiumcompound. Typically, the transmetalation reaction is performed in asuitable aprotic solvent at about −78 to about to abut 50° C. for about5 minutes to 24 hours. Non-limiting examples of suitable aproticsolvents include THF, dioxane and ether. In one embodiment, the moleratio of the compound of Formula V to organomagnesium compound is about1:1 to about 1:3, preferably about 1:2. In one embodiment, theorganomagnesium compound comprises an alkylmagnesium chloride, bromide,or iodide. In another embodiment, the organomagnesium compound comprises2-propylmagnesium chloride. In one embodiment, the organomagnesiumcompound comprises an alkylmagnesium chloride, bromide, or iodide andlithium chloride. In another embodiment, the organomagnesium compoundcomprises 2-propylmagnesium chloride and lithium chloride. In anotherembodiment, the organomagnesium compound is 2-propylmagnesium chlorideand lithium chloride in about a 1:1 mole ratio. In a preferredembodiment, the organomagnesium compound comprises 2-propylmagnesiumchloride and lithium chloride in a 1:1 mole ratio and the X³ of FormulaV is Br or I.

In another aspect wherein the compound of Formula IV is prepared bytreating a compound of Formula V with a organomagnesium compound, thecompound of Formula V may be treated with more than one organomagnesiumcompound. This procedure would be preferable when the compound ofFormula V comprises a substituent with an acidic hydrogen. Non-limitingexamples of the substituents with acidic hydrogens are NH₂, OH, SH,NH(C₁-C₆ alkyl) and the like. One skilled in the art will recognize thatthe acidic hydrogen group of the substituent of the compound of FormulaV will consume one mole equivalent of the organomagnesium compound. Theorganomagnesium compound consumed may be different from theorganomagnesium compound that produces the transmetalation reaction. Forexample, but not by way of limitation, treating the compound of FormulaV with about one mole equivalent of methylmagnesium chloride wouldneutralize an acidic hydrogen of NH(C₁-C₆ alkyl), OH, or SH substituentby forming a magnesium salt and the X³ group (Cl, Br, or I group) of thecompound of Formula V may be transmetalated with another organomagnesiumcompound such as 2-propylmagnesium chloride or 2-propylmagnesiumchloride and lithium chloride. Similarly, if additional acidic hydrogensare present, an additional about equivalent amount of organomagnesiumcompound would be required to neutralize each additional acidichydrogen, e.g., each additional NH₂ substituent would require about twoadditional equivalents of organomagnesium compound. Typically, thetransmetalation reactions of this aspect are performed in a suitableaprotic solvent at about −78 to about to abut 50° C. for about 5 minutesto 24 hours. Non-limiting examples of suitable aprotic solvents includeTHF, dioxane and ether. In one embodiment, the compound of Formula IV isprepared by treating the compound of Formula V with about one moleequivalent of a first organomagnesium compound for each acidic hydrogenin a substitutent followed by treatment with a second organomagnesiumcompound to transmetallate the X³ group of Formula V. In one embodiment,the mole ratio of the first organomagnesium compound to each acidhydrogen in a substituent of a molecule of Formula V is about 1:1 toabout 1:1.4 and the mole ratio of the second organomagnesium compound tothe compound of Formula V is about 1:0.8 to about 1:2. In oneembodiment, the first organomagnesium compound comprises analkylmagnesium chloride, bromide, or iodide. In another embodiment, thefirst organomagnesium compound comprises methylmagnesium chloride. Inanother embodiment, the second organomagnesium compound comprises analkylmagnesium chloride, bromide, or iodide. In another embodiment, thesecond alkylmagnesium compound comprises 2-propylmagnesium chloride. Inone embodiment, the second organomagnesium compound comprises analkylmagnesium chloride, bromide, or iodide and lithium chloride. Inanother embodiment the second organomagnesium compound is2-propylmagnesium chloride and lithium chloride in a 1:1 mole ratio. Ina preferred embodiment, the first organomagnesium compound ismethylmagnesium chloride and the second organomagnesium compoundcomprises 2-propylmagnesium chloride. In another preferred embodimentthe first organomagnesium compound is methylmagnesium chloride and thesecond organomagnesium compound is 2-propylmagnesium chloride andlithium chloride in a 1:1 mole ratio. In another preferred embodimentthe first organomagnesium compound is methylmagnesium chloride, thesecond organomagnesium compound is 2-propylmagnesium chloride andlithium chloride in about 1:1 mole ratio, and the X³ of Formula V is Bror I. In another preferred embodiment the first organomagnesium compoundis methylmagnesium chloride, the second organomagnesium compound is2-propylmagnesium chloride and lithium chloride in about 1:1 mole ratio,the X³ of Formula V is Br or I. and R⁸ is NH₂.

The magnesium salts of the substituents of Formula V discussed above maybe converted to a protected form of the substituent such as, but notlimited to, a silyl protected substituent. Subsequently, the X³ group(Cl, Br, or I group) of the compound of Formula V may be transmetalatedwith the same or a different organomagnesium compound such as2-propylmagnesium chloride or 2-propylmagnesium chloride and lithiumchloride. Similarly, if additional acidic hydrogens are present, anadditional about one equivalent amount of organomagnesium compound wouldbe required to neutralize each additional acidic hydrogen, e.g., eachadditional NH₂ substituent would require about two additionalequivalents of organomagnesium compound and the resulting magnesiumsalts could be converted to protecting groups, such as but not limitedto, silyl protecting groups. Non-limiting examples of the resultingprotected substituents would be OSi(R³)₃, SSi(R³)₃, N[Si(R³)₃][C₁-C₆alkyl], N[Si(R³)₂(CH₂)₂ Si(R³)₂] and N[Si(R³)₃]₂. All such intermediateswith protected substituents are within the scope of the instantinvention. Non-limiting examples of silylating reagents to convert theintermediate magnesium salt of the substituents to protectedsubstituents include X³Si(R³)₃, X³Si(R³)₂(CH₂)₂ Si(R³)₂X³ and(R²⁰)₃CS(O)₂OSi(R³)₃; more specifically ClSi(R³)₃, ClSi(R³)₂(CH₂)₂Si(R³)₂Cl and CF₃S(O)₂OSi(R³)₃; and most specifically ClSi(CH₃)₃,ClSi(CH₃)₂(CH₂)₂ Si(CH₃)₂Cl and CF₃S(O)₂OSi(CH₃)₃. These silylatingreagents may be present before the addition of the initialorganometallic agent if the temperature of the reaction is sufficientlycontrolled or they may be added after conversion of the substituent tothe magnesium salt.

Typically, the conversion of substituents of Formula V with acidichydrogens to protected substituents are performed in a suitable aproticsolvent at about −78 to about to abut 50° C. for about 5 minutes to 24hours. Non-limiting examples of suitable aprotic solvents include THF,dioxane and ether.

In one embodiment, the compound of Formula IV is prepared by treatingthe compound of Formula V comprising substituents with acidic hydrogenswith about one mole equivalent of a first organomagnesium compound foreach acidic hydrogen in a substitutent, treatment with about 1-1.4equivalents of protecting group reagent for each acid hydrogen, andtreatment with 1-2 equivalents of the same or a differentorganomagnesium compound to transmetallate the X³ group of Formula V.

In another embodiment, the compound of Formula IV is prepared bytreating a mixture of compound of Formula V and about 1-1.4 equivalentsof protecting group reagent per acidic hydrogen in Formula V with about1-1.4 equivalents of a first organomagnesium compound for each acidhydrogen in a substitutent, followed by treatment with 1-2 equivalentsof the same or a different organomagnesium compound to transmetallatethe X³ group of Formula V.

In another embodiment, the compound of Formula IV is prepared bytreating a mixture of compound of Formula V and about 1-1.4 equivalentsof protecting reagent per acidic hydrogen in Formula V with about 1-1.4equivalents of a organomagnesium compound for each acid hydrogen in asubstitutent and an additional 1-2 equivalents of organomagnesiumcompound to transmetallate the X³ group of Formula V. In another aspectof this embodiment, the X³ of Formula V is Br or I and R⁸ of Formula Vis NH₂.

In another embodiment, the method of preparing a compound of Formula Ior Formula Ib further comprises a method of preparing a compound ofFormula IV wherein M is Li by treating a compound of Formula V with anorganolithium compound. Typically, the transmetalation reaction isperformed in a suitable aprotic solvent at about −100 to about to abut20 OC for about 5 minutes to 24 hours. Non-limiting examples of suitableaprotic solvents include THF and ether. In one aspect of thisembodiment, the mole ratio of the compound of Formula V to organolithiumcompound is about 1:1 to about 1:3, preferably about 1:1.4. In anotheraspect of this embodiment, the organolithium compound comprises analkyllithium compound. In another aspect of this embodiment, theorganolithium compound comprises n-butyllithium. In another aspect ofthis embodiment, the organolithium compound comprises iso-butyllithium.In another aspect of this embodiment, the organolithium compoundcomprises tert-butyllithium. In a preferred aspect of this embodiment,the organolithium compound comprises an alkyllithium compound and the X³of Formula V is Br or I.

In another embodiment wherein the compound of Formula IV is prepared bytreating a compound of Formula V with an organolithium compound, thecompound of Formula V may be treated with more than one mole equivalentof organolithium compound. This procedure would be preferable when thecompound of Formula V is comprised of a substituent with an acidichydrogen. Non-limiting examples of the substituents with acidichydrogens are NH₂, OH, SH, NH(C₁-C₆ alkyl) and the like. One skilled inthe art will recognize that the acidic hydrogen group of the substituentof the compound of Formula V will consume one mole equivalent of theorganolithium compound. For example, but not by way of limitation,treating the compound of Formula V with about one mole equivalent oforganolithium compound would neutralize an acidic hydrogen of NH(C₁-C₆alkyl), OH, or SH substituent by forming a lithium salt and the X³ group(Cl, Br, or I group) of the compound of Formula V may be transmetalatedwith another mole equivalent of organolithium compound. Similarly, ifadditional acidic hydrogens are present, an additional about equivalentamount of organolithium compound would be required to neutralize eachadditional acidic hydrogen, e.g., each additional NH₂ substituent wouldrequire about two additional equivalents of organolithium compound.Typically, the transmetalation reactions of this aspect are performed ina suitable aprotic solvent at about −100 to about to abut 20° C. forabout 5 minutes to 24 hours. Non-limiting examples of suitable aproticsolvents include THF, dioxane and ether. In one embodiment, the moleratio of the organolithium compound to the each acid hydrogen in asubstituent of a molecule of Formula V is about 1:1 to about 1:1.4 andthe mole ratio of the additional amount of organolithium compound to thecompound of Formula V is about 1:0.8 to about 1:1.4. In another aspectof this embodiment, the organolithium compound comprises an alkyllithiumcompound. In another embodiment, the organolithium compound comprisesn-butyllithium. In another embodiment, the organolithium compoundcomprises iso-butyllithium. In another embodiment, the organolithiumcompound comprises tert-butyllithium. In a preferred embodiment, theorganolithium compound comprises a (C₁-C₆)alkyllithium compound and theX³ of Formula V is Br or I.

The lithium salts of the substituents of Formula V discussed above maybe converted to a protected form of the substituent such as, but notlimited to, a silyl protected substituent. Subsequently, the X³ group(Cl, Br, or I group) of the compound of Formula V may be transmetalatedwith the same or a different organolithium compound. Similarly, ifadditional acidic hydrogens are present, an additional about oneequivalent amount of organolithium compound would be required toneutralize each additional acidic hydrogen, e.g., each additional NH₂substituent would require about two additional equivalents oforganolithium compound and the resulting lithium salts could beconverted to protecting groups, such as but not limited to, silylprotecting groups. Non-limiting examples of the resulting protectedsubstituents would be OSi(R³)₃, SSi(R³)₃, N[Si(R³)₃][C₁-C₆ alkyl],N[Si(R³)₂(CH₂)₂ Si(R³)₂] and N[Si(R³)₃]₂. All such intermediates withprotected substituents are within the scope of the instant invention.Non-limiting examples of silylating reagents to convert the intermediatelithium salt of the substituents to protected substituents includeX³Si(R³)₃, X³Si(R³)₂(CH₂)₂ Si(R³)₂X³ and (R²⁰)₃CS(O)₂OSi(R³)₃; morespecifically ClSi(R³)₃, ClSi(R³)₂(CH₂)₂ Si(R³)₂Cl and CF₃S(O)₂OSi(R³)₃,and most specifically ClSi(CH₃)₃, ClSi(CH₃)₂(CH₂)₂ Si(CH₃)₂C₁ andCF₃S(O)₂OSi(CH₃)₃. These silylating reagents may be present before theaddition of the initial organometallic agent if the temperature of thereaction is sufficiently controlled or they may be added afterconversion of the substituent to the lithium salt.

Typically, the conversion of substituents of Formula V with acidhydrogens to protected substituents are performed in a suitable aproticsolvent at about −100 to about to abut 20° C. for about 5 minutes to 24hours. Non-limiting examples of suitable aprotic solvents include THF,dioxane and ether.

In one embodiment, the compound of Formula IV is prepared by treatingthe compound of Formula V comprising substituents with acid hydrogenswith about 1-1.4 mole equivalent of a organolithium compound for eachacid hydrogen in a substitutent, treatment with about 1-1.4 equivalentsof protecting group reagent for each acid hydrogen, and treatment with1-1.4 equivalents of the same or a different organolithium compound totransmetallate the X³ group of Formula V.

In another embodiment, the compound of Formula IV is prepared bytreating a mixture of compound of Formula V and about 1-1.4 equivalentsof protecting group reagent per acidic hydrogen in Formula V with about1-1.4 equivalents of a first organolithium compound for each acidhydrogen in a substitutent, followed by treatment with 1-1.4 equivalentsof the same or a different organolithium compound to transmetallate theX³ group of Formula V.

In another embodiment, the compound of Formula IV is prepared bytreating a mixture of compound of Formula V and about 1-1.4 equivalentsof protecting reagent per acidic hydrogen in Formula V with about 1-1.4equivalents of a organolithium compound for each acid hydrogen in asubstitutent and an additional 1-1.4 equivalents of organolithiumcompound to transmetallate the X³ group of Formula V. In another aspectof this embodiment, the X³ of Formula V is Br or I. and R⁸ of Formula Vis NH₂. In another aspect of this embodiment, the organolithium compoundcomprises an alkyllithium compound. In another embodiment, theorganolithium compound comprises n-butyllithium. In another embodiment,the organolithium compound comprises iso-butyllithium. In anotherembodiment, the organolithium compound comprises tert-butyllithium. In apreferred embodiment, the organolithium compound comprises a(C₁-C₆)alkyllithium compound and the X³ of Formula V is Br or I. Inanother embodiment, the protecting group reagent is a silylatingreagent. In another embodiment, the protecting group reagent isX³Si(R³)₃ or (R²⁰)₃CS(O)₂OSi(R³)₃. In another embodiment, the protectinggroup reagent is ClSi(R³)₃ or CF₃S(O)₂OSi(R³)₃. In another embodiment,the protecting group reagent is ClSi(CH₃)₃ or CF₃S(O)₂OSi(CH₃)₃.

In another embodiment, provided are useful intermediates for thesyntheses of compounds of Formula I represented by Formula VI. In oneembodiment, R¹⁷ is OH.

In another embodiment, R¹⁷ is —OC(O)R¹⁸. In another embodiment, R¹⁷ is—OC(O)OR¹⁸. In another embodiment, R¹⁷ is OR¹⁸.

In another embodiment, provided is a compound of Formula IIb representedby Formula VIb:

or an acceptable salt, thereof;

wherein the variables are defined as for Formula VI.

In one embodiment of the compound of Formula VIb, R¹⁷ is OH. Thefollowing are additional independent aspects of this embodiment:

(a) R¹ is H. R¹ is CH₃.

(b) X¹ is C—R¹⁰. X¹ is C—H. X¹ is N.

(c) R⁸ is NR¹¹R¹². R⁸ is OR¹¹. R⁸ is SR¹¹

(d) R⁹ is H. R⁹ is NR¹¹R¹². R⁹ is SR¹¹

(e) R^(2b) is OR⁴. R^(2b) is F. Each R^(2a) and R^(2b) is independentlyOR⁴. R^(2a) is OR⁴ and R^(2b) is F. R^(2a) is OR⁴, R^(2b) is F and R⁴ isC(O)R⁵. R^(2a) is OR⁴, R^(2b) is F and R⁴ is C(O)R⁵ wherein R⁵ is phenylor substituted phenyl. R^(2b) is OR⁴ wherein R⁴ is C(R⁵)₂R⁶ and R⁶ isphenyl or substituted phenyl. R^(2b) is OR⁴ wherein R⁴ is CH₂R⁶ and R⁶is phenyl. R^(2b) is OR⁴ wherein R⁴ is CH₂R⁶ and R⁶ is substitutedphenyl. Each R^(2a) and R^(2b) is OR⁴ wherein each R⁴ is independentlyC(R⁵)₂R⁶ and R⁶ is phenyl or substituted phenyl. Each R^(2a) and R^(2b)is OR⁴ wherein each R⁴ is CH₂R⁶ and R⁶ is phenyl. Each R^(2a) and R^(2b)is OR⁴ wherein each R⁴ is CH₂R⁶ and each R⁶ is independently substitutedphenyl. Each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ taken togetherare —C(R¹⁹)₂—. Each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —C(CH₃)₂—. Each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴taken together are —CH(R¹⁹)—. Each R^(2a) and R^(2b) is OR⁴ wherein thetwo R⁴ taken together are —CH(R¹⁹)— wherein R¹⁹ is phenyl or substitutedphenyl. R^(2a) is OR⁴ wherein R⁴ is C(R⁵)₂R⁶, R⁶ is phenyl orsubstituted phenyl and R^(2b) is F. R^(2a) is H.

(f) R⁷ is C(O)R⁵. R⁷ is C(R⁵)₂R⁶ and R⁶ is phenyl or substituted phenyl.R⁷ is CH₂R⁶ and R⁶ is phenyl. R⁷ is CH₂R⁶ and R⁶ is substituted phenyl.R⁷ is C(R⁵)₂R⁶ and each R⁵ and R⁶ is independently phenyl or substitutedphenyl. R⁷ is Si(R³)₃. R⁷ is Si(R³)₂(t-butyl) wherein each R³ is CH₃. R⁷is Si(R³)₂(t-butyl) wherein each R³ is independently phenyl orsubstituted phenyl. R⁷ is tetrahydro-2H-pyran-2-yl. R⁷ is C(R⁵)₂R⁶wherein each R⁵ and R⁶ is independently phenyl or substituted phenyl andeach R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ taken together are—C(CH₃)₂—. R⁷ is Si(R³)₃ and each R^(2a) and R^(2b) is OR⁴ wherein thetwo R⁴ taken together are —C(CH₃)₂—. R⁷ is Si(R³)₂(t-butyl) wherein eachR³ is CH₃ and each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —C(CH₃)₂—. R⁷ is Si(R³)₂(t-butyl) wherein each R³ isindependently phenyl or substituted phenyl and each R^(2a) and R^(2b) isOR⁴ wherein the two R⁴ taken together are —C(CH₃)₂—. R⁷ istetrahydro-2H-pyran-2-yl and each R^(2a) and R^(2b) is OR⁴ wherein thetwo R⁴ taken together are —C(CH₃)₂—. R⁷ is C(O)R⁵ and each R^(2a) andR^(2b) is OR⁴ wherein the two R⁴ taken together are —C(CH₃)₂—. R⁷ isC(R⁵)₂R⁶ wherein each R⁵ and R⁶ is independently phenyl or substitutedphenyl and each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —CH(R¹⁹)— wherein R¹⁹ is phenyl or substituted phenyl. R⁷is Si(R³)₃ and each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —CH(R¹⁹)— wherein R¹⁹ is phenyl or substituted phenyl. R⁷is Si(R³)₂(t-butyl) wherein each R³ is CH₃ and each R^(2a) and R^(2b) isOR⁴ wherein the two R⁴ taken together are —CH(R¹⁹)— wherein R¹⁹ isphenyl or substituted phenyl. R⁷ is Si(R³)₂(t-butyl) wherein each R³ isindependently phenyl or substituted phenyl and each R^(2a) and R^(2b) isOR⁴ wherein the two R⁴ taken together are —CH(R¹⁹)— wherein R¹⁹ isphenyl or substituted phenyl. R⁷ is tetrahydro-2H-pyran-2-yl and eachR^(2a) and R^(2b) is OR⁴ wherein the two R⁴ taken together are —CH(R¹⁹)—wherein R¹⁹ is phenyl or substituted phenyl. R⁷ is C(O)R⁵ and eachR^(2a) and R^(2b) is OR⁴ wherein the two R⁴ taken together are —CH(R¹⁹)—wherein R¹⁹ is phenyl or substituted phenyl. R⁷ is C(O)R⁵ wherein R⁵ isphenyl or substituted phenyl and R^(2b) is F.

(g) R¹ is H, X¹ is CH, and R⁸ is NR¹¹R¹². R¹ is H, X¹ is CH, and R⁸ isNH₂. R¹ is CH₃, X¹ is CH, and R⁸ is NR¹¹R¹². R¹ is CH₃, X¹ is CH, and R⁸is NH₂. R¹ is H, X¹ is N, and R⁸ is NR¹¹R¹². R¹ is H, X¹ is N, and R⁸ isNH₂. R¹ is CH₃, X¹ is N, and R⁸ is NR¹¹R¹². R¹ is CH₃, X¹ is N, and R⁸is NH₂. R¹ is H, X¹ is CH, and R⁹ is NR¹¹R¹². R¹ is H, X¹ is CH, and R⁹is NH₂. R¹ is H, X¹ is CH, and R⁹ is SR¹¹. R¹ is H, X¹ is CH, and R⁹ isSH. R¹ is H, X¹ is CH, and R⁹ is H. R¹ is CH₃, X¹ is CH, and R⁹ isNR¹¹R¹². R¹ is CH₃, X¹ is CH, and R⁹ is NH₂. R¹ is CH₃, X¹ is CH, and R⁹is SR¹¹. R¹ is CH₃, X¹ is CH, and R⁹ is SH. R¹ is CH₃, X¹ is CH, and R⁹is H.

(h) R¹ is H, X¹ is CH, and R⁸ is OR¹¹. R¹ is H, X¹ is CH, and R⁸ is OH.R¹ is CH₃, X¹ is CH, and R⁸ is OR¹¹. R¹ is CH₃, X¹ is CH, and R⁸ is OH.R¹ is H, X¹ is N, and R⁸ is OR¹¹. R¹ is H, X¹ is N, and R⁸ is OH. R¹ isCH₃, X¹ is N, and R⁸ is OR¹¹. R¹ is CH₃, X¹ is N, and R⁸ is OH.

(i) R¹ is H, X¹ is CH, and R⁸ is SR¹¹. R¹ is H, X¹ is CH, and R⁸ is SH.R¹ is CH₃, X¹ is CH, and R⁸ is SR¹¹. R¹ is CH₃, X¹ is CH, and R⁸ is SH.R¹ is H, X¹ is N, and R⁸ is SR¹¹. R¹ is H, X¹ is N, and R⁸ is SH. R¹ isCH₃, X¹ is N, and R⁸ is SR¹¹. R¹ is CH₃, X¹ is N, and R⁸ is SH.

(j) R¹ is H, X¹ is CH, R⁹ is H and R⁸ is NR¹¹R¹². R¹ is H, X¹ is CH, R⁹is H and R⁸ is NH₂. R¹ is CH₃, X¹ is CH, R⁹ is H and R⁸ is NR¹¹R¹². R¹is CH₃, X¹ is CH, R⁹ is H and R⁸ is NH₂. R¹ is H, X¹ is N, R⁹ is H andR⁸ is NR¹¹R¹². R¹ is H, X¹ is N, R⁹ is H and R⁸ is NH₂. R¹ is CH₃, X¹ isN, R⁹ is H and R⁸ is NR¹¹R¹². R¹ is CH₃, X¹ is N, R⁹ is H and R⁸ is NH₂.R¹ is H, X¹ is CH, R⁹ is NR¹¹R¹² and R⁸ is NR¹¹R¹². R¹ is H, X¹ is CH,R⁹ is NR¹¹R¹² and R⁸ is NH₂. R¹ is CH₃, X¹ is CH, R⁹ is NR¹¹R¹² and R⁸is NR¹¹R¹². R¹ is CH₃, X¹ is CH, R⁹ is NR¹¹R¹² and R⁸ is NH₂. R¹ is H,X¹ is N, R⁹ is NR¹¹R¹² and R⁸ is NR¹¹R¹². R¹ is H, X¹ is N, R⁹ isNR¹¹R¹² and R⁸ is NH₂. R¹ is CH₃, X¹ is N, R⁹ is NR¹¹R¹² and R⁸ isNR¹¹R¹². R¹ is CH₃, X¹ is N, R⁹ is NR¹¹R¹² and R⁸ is NH₂.

(k) R¹ is H, X¹ is CH, and R⁸ and R⁹ are independently SR¹¹. R¹ is CH₃,X¹ is CH, and R⁸ and R⁹ are independently SR¹¹. R¹ is H, X¹ is N, and R⁸and R⁹ are independently SR¹¹. R¹ is CH₃, X¹ is N, and R⁸ and R⁹ areindependently SR¹¹

In one embodiment of the compound of Formula VIb, R¹⁷ is —OR¹⁸. Thefollowing are additional independent aspects of this embodiment:

(a) R¹ is H. R¹ is CH₃.

(b) X¹ is C—R¹⁰. X¹ is C—H. X¹ is N.

(c) R⁸ is NR¹¹R¹². R⁸ is OR¹¹. R⁸ is SR¹¹

(d) R⁹ is H. R⁹ is NR¹¹R¹². R⁹ is SR¹¹

(e) R^(2b) is OR⁴. R^(2b) is F. Each R^(2a) and R^(2b) is independentlyOR⁴. R^(2a) is OR⁴ and R^(2b) is F. R^(2a) is OR⁴, R^(2b) is F and R⁴ isC(O)R⁵. R^(2a) is OR⁴, R^(2b) is F and R⁴ is C(O)R⁵ wherein R⁵ is phenylor substituted phenyl. R^(2b) is OR⁴ wherein R⁴ is C(R⁵)₂R⁶ and R⁶ isphenyl or substituted phenyl. R^(2b) is OR⁴ wherein R⁴ is CH₂R⁶ and R⁶is phenyl. R^(2b) is OR⁴ wherein R⁴ is CH₂R⁶ and R⁶ is substitutedphenyl. Each R^(2a) and R^(2b) is OR⁴ wherein each R⁴ is independentlyC(R⁵)₂R⁶ and R⁶ is phenyl or substituted phenyl. Each R^(2a) and R^(2b)is OR⁴ wherein each R⁴ is CH₂R⁶ and R⁶ is phenyl. Each R^(2a) and R^(2b)is OR⁴ wherein each R⁴ is CH₂R⁶ and each R⁶ is independently substitutedphenyl. Each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ taken togetherare —C(R¹⁹)₂—. Each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —C(CH₃)₂—. Each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴taken together are —CH(R¹⁹)—. Each R^(2a) and R^(2b) is OR⁴ wherein thetwo R⁴ taken together are —CH(R¹⁹)— wherein R¹⁹ is phenyl or substitutedphenyl. R^(2a) is OR⁴ wherein R⁴ is C(R⁵)₂R⁶, R⁶ is phenyl orsubstituted phenyl and R^(2b) is F. R^(2a) is H.

(f) R⁷ is C(O)R⁵. R⁷ is C(R⁵)₂R⁶ and R⁶ is phenyl or substituted phenyl.R⁷ is CH₂R⁶ and R⁶ is phenyl. R⁷ is CH₂R⁶ and R⁶ is substituted phenyl.R⁷ is C(R⁵)₂R⁶ and each R⁵ and R⁶ is independently phenyl or substitutedphenyl. R⁷ is Si(R³)₃. R⁷ is Si(R³)₂(t-butyl) wherein each R³ is CH₃. R⁷is Si(R³)₂(t-butyl) wherein each R³ is independently phenyl orsubstituted phenyl. R⁷ is tetrahydro-2H-pyran-2-yl. R⁷ is C(R⁵)₂R⁶wherein each R⁵ and R⁶ is independently phenyl or substituted phenyl andeach R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ taken together are—C(CH₃)₂—. R⁷ is Si(R³)₃ and each R^(2a) and R^(2b) is OR⁴ wherein thetwo R⁴ taken together are —C(CH₃)₂—. R⁷ is Si(R³)₂(t-butyl) wherein eachR³ is CH₃ and each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —C(CH₃)₂—. R⁷ is Si(R³)₂(t-butyl) wherein each R³ isindependently phenyl or substituted phenyl and each R^(2a) and R^(2b) isOR⁴ wherein the two R⁴ taken together are —C(CH₃)₂—. R⁷ istetrahydro-2H-pyran-2-yl and each R^(2a) and R^(2b) is OR⁴ wherein thetwo R⁴ taken together are —C(CH₃)₂—. R⁷ is C(O)R⁵ and each R^(2a) andR^(2b) is OR⁴ wherein the two R⁴ taken together are —C(CH₃)₂—. R⁷ isC(R⁵)₂R⁶ wherein each R⁵ and R⁶ is independently phenyl or substitutedphenyl and each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —CH(R¹⁹)— wherein R¹⁹ is phenyl or substituted phenyl. R⁷is Si(R³)₃ and each R^(2a) and R^(2b) is OR⁴ wherein the two R⁴ takentogether are —CH(R¹⁹)— wherein R¹⁹ is phenyl or substituted phenyl. R⁷is Si(R³)₂(t-butyl) wherein each R³ is CH₃ and each R^(2a) and R^(2b) isOR⁴ wherein the two R⁴ taken together are —CH(R¹⁹)— wherein R¹⁹ isphenyl or substituted phenyl. R⁷ is Si(R³)₂(t-butyl) wherein each R³ isindependently phenyl or substituted phenyl and each R^(2a) and R^(2b) isOR⁴ wherein the two R⁴ taken together are —CH(R¹⁹)— wherein R¹⁹ isphenyl or substituted phenyl. R⁷ is tetrahydro-2H-pyran-2-yl and eachR^(2a) and R^(2b) is OR⁴ wherein the two R⁴ taken together are —CH(R¹⁹)—wherein R¹⁹ is phenyl or substituted phenyl. R⁷ is C(O)R⁵ and eachR^(2a) and R^(2b) is OR⁴ wherein the two R⁴ taken together are —CH(R¹⁹)—wherein R¹⁹ is phenyl or substituted phenyl. R⁷ is C(O)R⁵ wherein R⁵ isphenyl or substituted phenyl and R^(2b) is F.

(g) R¹⁸ is (C₁-C₈)alkyl or substituted (C₁-C₈)alkyl. R¹⁸ is(C₁-C₈)alkyl. R¹⁸ is methyl.

(h) R¹ is H, X¹ is CH, and R⁸ is NR¹¹R¹². R¹ is H, X¹ is CH, and R⁸ isNH₂. R¹ is CH₃, X¹ is CH, and R⁸ is NR¹¹R¹². R¹ is CH₃, X¹ is CH, and R⁸is NH₂. R¹ is H, X¹ is N, and R⁸ is NR¹¹R¹². R¹ is H, X¹ is N, and R⁸ isNH₂. R¹ is CH₃, X¹ is N, and R⁸ is NR¹¹R¹². R¹ is CH₃, X¹ is N, and R⁸is NH₂. R¹ is H, X¹ is CH, and R⁹ is NR¹¹R¹². R¹ is H, X¹ is CH, and R⁹is NH₂. R¹ is H, X¹ is CH, and R⁹ is SR¹¹. R¹ is H, X¹ is CH, and R⁹ isSH. R¹ is H, X¹ is CH, and R⁹ is H. R¹ is CH₃, X¹ is CH, and R⁹ isNR¹¹R¹². R¹ is CH₃, X¹ is CH, and R⁹ is NH₂. R¹ is CH₃, X¹ is CH, and R⁹is SR¹¹. R¹ is CH₃, X¹ is CH, and R⁹ is SH. R¹ is CH₃, X¹ is CH, and R⁹is H.

(i) R¹ is H, X¹ is CH, and R⁸ is OR¹¹. R¹ is H, X¹ is CH, and R⁸ is OH.R¹ is CH₃, X¹ is CH, and R⁸ is OR¹¹. R¹ is CH₃, X¹ is CH, and R⁸ is OH.R¹ is H, X¹ is N, and R⁸ is OR¹¹. R¹ is H, X¹ is N, and R⁸ is OH. R¹ isCH₃, X¹ is N, and R⁸ is OR¹¹. R¹ is CH₃, X¹ is N, and R⁸ is OH.

(j) R¹ is H, X¹ is CH, and R⁸ is SR¹¹. R¹ is H, X¹ is CH, and R⁸ is SH.R¹ is CH₃, X¹ is CH, and R⁸ is SR¹¹. R¹ is CH₃, X¹ is CH, and R⁸ is SH.R¹ is H, X¹ is N, and R⁸ is SR¹¹. R¹ is H, X¹ is N, and R⁸ is SH. R¹ isCH₃, X¹ is N, and R⁸ is SR¹¹. R¹ is CH₃, X¹ is N, and R⁸ is SH.

(k) R¹ is H, X¹ is CH, R⁹ is H and R⁸ is NR¹¹R¹². R¹ is H, X¹ is CH, R⁹is H and R⁸ is NH₂. R¹ is CH₃, X¹ is CH, R⁹ is H and R⁸ is NR¹¹R¹². R¹is CH₃, X¹ is CH, R⁹ is H and R⁸ is NH₂. R¹ is H, X¹ is N, R⁹ is H andR⁸ is NR¹¹R¹². R is H, X¹ is N, R⁹ is H and R⁸ is NH₂. R¹ is CH₃, X¹ isN, R⁹ is H and R⁸ is NR¹¹R¹². R¹ is CH₃, X¹ is N, R⁹ is H and R⁸ is NH₂.R¹ is H, X¹ is CH, R⁹ is NR¹¹R¹² and R⁸ is NR¹¹R¹². R¹ is H, X¹ is CH,R⁹ is NR¹¹R¹² and R⁸ is NH₂. R¹ is CH₃, X¹ is CH, R⁹ is NR¹¹R¹² and R⁸is NR¹¹R¹². R¹ is CH₃, X¹ is CH, R⁹ is NR¹¹R¹² and R⁸ is NH₂. R¹ is H,X¹ is N, R⁹ is NR¹¹R¹² and R⁸ is NR¹¹R¹². R¹ is H, X¹ is N, R⁹ isNR¹¹R¹² and R⁸ is NH₂. R¹ is CH₃, X¹ is N, R⁹ is NR¹¹R¹² and R⁸ isNR¹¹R¹². R¹ is CH₃, X¹ is N, R⁹ is NR¹¹R¹² and R⁸ is NH₂.

(l) R¹ is H, X¹ is CH, and R⁸ and R⁹ are independently SR¹¹. R¹ is CH₃,X¹ is CH, and R⁸ and R⁹ are independently SR¹¹. R¹ is H, X¹ is N, and R⁸and R⁹ are independently SR¹¹. R¹ is CH₃, X¹ is N, and R⁸ and R⁹ areindependently SR¹¹

In another embodiment, the compound of Formula VIb is a compound ofFormula VIc

or an acceptable salt thereof,wherein:

R^(2b) is OR⁴ or F;

each R⁴ is independently —CH₂R⁶ or C(O)R⁵ wherein R⁵ is phenyl orsubstituted phenyl;

R⁷ is Si(R³)₃, C(O)R⁵ or —C(R⁵)₂R⁶ wherein each R⁵ is independently H,phenyl, or substituted phenyl;

R⁶ is phenyl or substituted phenyl; and

the remaining variables are defined as in Formula VI.

In one aspect of this embodiment, R^(2b) is OR⁴. In another aspect ofthis embodiment, R^(2b) is F. In another aspect of this embodiment, R⁷is —CH₂R⁶. In another aspect of this embodiment, R⁷ is C(O)R⁵ wherein R⁵is phenyl or substituted phenyl. In another aspect of this embodiment,R^(2b) is F and each R⁴ and R⁷ is C(O)R⁵ wherein each R⁵ isindependently phenyl or substituted phenyl. In another aspect of thisembodiment, R¹⁷ is OH. In another aspect of this embodiment, R¹⁷ isOR¹⁸. In another aspect of this embodiment, R¹⁷ is —OC(O)R¹⁸. In anotheraspect of this embodiment, R¹⁷ is —OC(O)CH₃. In another aspect of thisembodiment, R¹⁷ is ethoxy or methoxy. In another aspect of thisembodiment, X¹ is C—R¹⁰. In another aspect of this embodiment, X¹ isC—H. In another aspect of this embodiment, X¹ is N. In another aspect ofthis embodiment, R¹ is H. In another aspect of this embodiment, R¹ isCH₃. In another aspect of this embodiment, R¹⁷ is OH and X¹ is C—R¹⁰. Inanother aspect of this embodiment, R¹⁷ is —OC(O)R¹⁸ and X¹ is C—R¹⁰. Inanother aspect of this embodiment, R¹⁷ is —OC(O)CH₃ and X¹ is C—R¹⁰. Inanother aspect of this embodiment, R¹⁷ is OR¹⁸ and X¹ is C—R¹⁰. Inanother aspect of this embodiment, R¹⁷ is OH and X¹ is C—H. In anotheraspect of this embodiment, R¹⁷ is —OC(O)R¹⁸ and X¹ is C—H. In anotheraspect of this embodiment, R¹⁷ is —OC(O)CH₃ and X¹ is C—H. In anotheraspect of this embodiment, R¹⁷ is OR¹⁸ and X¹ is C—H. In another aspectof this embodiment, R¹⁷ is OH and X¹ is N. In another aspect of thisembodiment, R¹⁷ is —OC(O)R¹⁸ and X¹ is N. In another aspect of thisembodiment, R¹⁷ is —OC(O)CH₃ and X¹ is N. In another aspect of thisembodiment, R¹⁷ is OR¹⁸ and X¹ is N. In another aspect of thisembodiment, R¹⁷ is OH, R¹ is H, and X¹ is C—R¹⁰. In another aspect ofthis embodiment, R¹⁷ is —OC(O)R¹⁸, R¹ is H and X¹ is C—R¹⁰. In anotheraspect of this embodiment, R¹⁷ is —OC(O)CH₃ R¹ is H and X¹ is C—R¹⁰. Inanother aspect of this embodiment, R¹⁷ is OR¹⁸, R¹ is H and X¹ is C—R¹⁰.In another aspect of this embodiment, R¹⁷ is OH, R¹ is H and X¹ is C—H.In another aspect of this embodiment, R¹⁷ is —OC(O)R¹⁸, R¹ is H and X¹is C—H. In another aspect of this embodiment, R¹⁷ is —OC(O)CH₃, R¹ is Hand X¹ is C—H. In another aspect of this embodiment, R¹⁷ is OR¹⁸, R¹ isH and X¹ is C—H. In another aspect of this embodiment, R¹⁷ is OH, R¹ isH and X¹ is N. In another aspect of this embodiment, R¹⁷ is —OC(O)R¹, R¹is H and X¹ is N. In another aspect of this embodiment, R¹⁷ is—OC(O)CH₃, R¹ is H and X¹ is N. In another aspect of this embodiment,R¹⁷ is OR¹⁸, R¹ is H and X¹ is N. In another aspect of this embodiment,R¹⁷ is OH, R¹ is CH₃, and X¹ is C—R¹⁰. In another aspect of thisembodiment, R¹⁷ is —OC(O)R¹⁸, R¹ is CH₃ and X¹ is C—R¹⁰. In anotheraspect of this embodiment, R¹⁷ is —OC(O)CH₃ R¹ is CH₃ and X¹ is C—R¹⁰.In another aspect of this embodiment, R¹⁷ is OR¹⁸, R¹ is CH₃ and X¹ isC—R¹⁰. In another aspect of this embodiment, R¹⁷ is OH, R¹ is CH₃ and X¹is C—H. In another aspect of this embodiment, R¹⁷ is —OC(O)R¹⁸, R¹ isCH₃ and X¹ is C—H. In another aspect of this embodiment, R¹⁷ is—OC(O)CH₃, R¹ is CH₃ and X¹ is C—H. In another aspect of thisembodiment, R¹⁷ is OR¹⁸, R¹ is CH₃ and X¹ is C—H. In another aspect ofthis embodiment, R¹⁷ is OH, R¹ is CH₃ and X¹ is N. In another aspect ofthis embodiment, R¹⁷ is —OC(O)R¹⁸, R¹ is CH₃ and X¹ is N. In anotheraspect of this embodiment, R¹⁷ is —OC(O)CH₃, R¹ is CH₃ and X¹ is N. Inanother aspect of this embodiment, R¹⁷ is OR¹⁸, R¹ is CH₃ and X¹ is N.

In another embodiment, the compound of Formula VIb is a compound ofFormula VId

or an acceptable salt thereof,

wherein:

-   -   each R¹⁹ is independently H, phenyl, substituted phenyl, or        methyl and R⁷ is —C(R⁵)₂R⁶, Si(R³)₃, C(O)R⁵, or

and the remaining variables are defined as in Formula VI.

In one aspect of this embodiment, R⁷ is CH₂R⁶ wherein R⁶ is phenyl orsubstituted phenyl. In one aspect of this embodiment, R⁷ is C(R⁵)₂R⁶wherein each R⁵ or R⁶ is independently phenyl or substituted phenyl. Inone aspect of this embodiment, R⁷ is Si(R³)₃. In one aspect of thisembodiment, R⁷ is Si(R³)₂(t-butyl) wherein each R³ is independentlyphenyl or substituted phenyl. In one aspect of this embodiment, R⁷ isSi(R³)₂(t-butyl) wherein each R³ is methyl. In one aspect of thisembodiment, R⁷ is C(O)R⁵. In one aspect of this embodiment, R⁷ isC(O)CH₃. In one aspect of this embodiment, R⁷ istetrahydro-2H-pyran-2-yl. In one aspect of this embodiment, each R¹⁹ isCH₃. In one aspect of this embodiment, one of R¹⁹ is H and the other ofR¹⁹ is phenyl or substituted phenyl. In one aspect of this embodiment,R⁷ is CH₂R⁶ wherein R⁶ is phenyl or substituted phenyl each R¹⁹ is CH₃.In one aspect of this embodiment, R⁷ is C(R⁵)₂R⁶ wherein each R⁵ or R⁶is independently phenyl or substituted phenyl and each R¹⁹ is CH₃. Inone aspect of this embodiment, R⁷ is Si(R³)₃ and each R¹⁹ is CH₃. In oneaspect of this embodiment, R⁷ is Si(R³)₂(t-butyl) wherein each R³ isindependently phenyl or substituted phenyl and each R¹⁹ is CH₃. In oneaspect of this embodiment, R⁷ is Si(R³)₂(t-butyl) wherein each R³ ismethyl and each R¹⁹ is CH₃. In one aspect of this embodiment, R⁷ isC(O)R⁵ and each R¹⁹ is CH₃. In one aspect of this embodiment, R⁷ isC(O)CH₃ and each R¹⁹ is CH₃. In one aspect of this embodiment, R⁷ istetrahydro-2H-pyran-2-yl and each R¹⁹ is CH₃.

In another embodiment of Formula VId, R¹⁷ is OH. In another embodimentof Formula VId, R¹⁷ is —OC(O)R¹⁸. In another embodiment of Formula VId,R¹⁷ is —OC(O)CH₃. In another embodiment of Formula VId, R¹⁷ is OR¹⁸. Inanother aspect of this embodiment, X¹ is C—R¹⁰. In another embodiment ofFormula VId, X¹ is C—H. In another embodiment of Formula VId, X¹ is N.In another embodiment of Formula VId, R¹ is H. In another embodiment ofFormula VId, R¹ is CH₃. In another embodiment of Formula VId, R¹⁷ is OHand X¹ is C—R¹⁰. In another embodiment of Formula VId, R¹⁷ is —OC(O)R¹⁸and X¹ is C—R¹⁰. In another embodiment of Formula VId, R¹⁷ is —OC(O)CH₃and X¹ is C—R¹⁰. In another embodiment of Formula VId, R¹⁷ is OR¹⁸ andX¹ is C—R¹⁰. In another embodiment of Formula VId, R¹⁷ is OH and X¹ isC—H. In another embodiment of Formula VId, R¹⁷ is —OC(O)R¹⁸ and X¹ isC—H. In another embodiment of Formula VId, R¹⁷ is —OC(O)CH₃ and X¹ isC—H. In another embodiment of Formula VId, R¹⁷ is OR¹⁸ and X¹ is C—H. Inanother embodiment of Formula VId, R¹⁷ is OH and X¹ is N. In anotherembodiment of Formula VId, R¹⁷ is —OC(O)R¹⁸ and X¹ is N. In anotherembodiment of Formula VId, R¹⁷ is —OC(O)CH₃ and X¹ is N. In anotherembodiment of Formula VId, R¹⁷ is OR¹⁸ and X¹ is N. In anotherembodiment of Formula VId, R¹⁷ is OH, R¹ is H, and X¹ is C—R¹⁰. Inanother embodiment of Formula VId, R¹⁷ is —OC(O)R¹⁸, R¹ is H and X¹ isC—R¹⁰. In another embodiment of Formula VId, R¹⁷ is —OC(O)CH₃ R¹ is Hand X¹ is C—R¹⁰. In another embodiment of Formula VId, R¹⁷ is OR¹⁸, R¹is H and X¹ is C—R¹⁰. In another embodiment of Formula VId, R¹⁷ is OH,R¹ is H and X¹ is C—H. In another aspect of this embodiment, R¹⁷ is—OC(O)R¹⁸, R¹ is H and X¹ is C—H. In another embodiment of Formula VId,R¹⁷ is —OC(O)CH₃, R¹ is H and X¹ is C—H. In another embodiment ofFormula VId, R¹⁷ is OR¹⁸, R¹ is H and X¹ is C—H. In another embodimentof Formula VId, R¹ is H and X¹ is N. In another embodiment of FormulaVId, R¹⁷ is —OC(O)R¹⁸, R¹ is H and X¹ is N. In another embodiment ofFormula VId, R¹⁷ is —OC(O)CH₃, R¹ is H and X¹ is N. In anotherembodiment of Formula VId, R¹⁷ is OR¹⁸, R¹ is H and X¹ is N. In anotherembodiment of Formula VId, R¹⁷ is OH, R¹ is CH₃, and X¹ is C—R¹⁰. Inanother embodiment of Formula VId, R¹⁷ is —OC(O)R¹⁸, R¹ is CH₃ and X¹ isC—R¹⁰. In another embodiment of Formula VId, R¹⁷ is —OC(O)CH₃ R¹ is CH₃and X¹ is C—R¹⁰. In another embodiment of Formula VId, R¹⁷ is OR¹⁸, R¹is CH₃ and X¹ is C—R¹⁰. In another embodiment of Formula VId, R¹⁷ is OH,R¹ is CH₃ and X¹ is C—H. In another embodiment of Formula VId, R¹⁷ is—OC(O)R¹⁸, R¹ is CH₃ and X¹ is C—H. In another embodiment of FormulaVId, R¹⁷ is —OC(O)CH₃, R¹ is CH₃ and X¹ is C—H. In another embodiment ofFormula VId, R¹⁷ is OR¹⁸, R¹ is CH₃ and X¹ is C—H. In another embodimentof Formula VId, R¹⁷ is OH, R¹ is CH₃ and X¹ is N. In another embodimentof Formula VId, R¹⁷ is —OC(O)R¹⁸, R¹ is CH₃ and X¹ is N. In anotherembodiment of Formula VId, R¹⁷ is —OC(O)CH₃, R¹ is CH₃ and X¹ is N. Inanother embodiment of Formula VId, R¹⁷ is OR¹⁸, R¹ is CH₃ and X¹ is N.

In another embodiment, the compound of Formula VIb is

or an acceptable salt thereof.

Definitions

Unless stated otherwise, the following terms and phrases as used hereinare intended to have the following meanings:

When trade names are used herein, applicants intend to independentlyinclude the tradename product and the active ingredient(s) of thetradename product.

As used herein, “a compound of the invention” or “a compound of FormulaI” means a compound of Formula I or an acceptable salt, thereof.Similarly, with respect to isolatable intermediates, the phrase “acompound of Formula (number)” means a compound of that formula and anacceptable salts, thereof.

“Alkyl” is hydrocarbon containing normal, secondary, tertiary or cycliccarbon atoms. For example, an alkyl group can have 1 to 20 carbon atoms(i.e., C₁-C₂₀ alkyl), 1 to 8 carbon atoms (i.e., C₁-C₈ alkyl), or 1 to 6carbon atoms (i.e., C₁-C₆ alkyl). Examples of suitable alkyl groupsinclude, but are not limited to, methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃),1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl,—CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl(i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃),2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl,—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, and octyl (—(CH₂)₇CH₃).

“Alkoxy” means a group having the formula —O-alkyl, in which an alkylgroup, as defined above, is attached to the parent molecule via anoxygen atom. The alkyl portion of an alkoxy group can have 1 to 20carbon atoms (i.e., C₁-C₂₀ alkoxy), 1 to 12 carbon atoms (i.e., C₁-C₁₂alkoxy), or 1 to 6 carbon atoms (i.e., C₁-C₆ alkoxy). Examples ofsuitable alkoxy groups include, but are not limited to, methoxy (—O—CH₃or —OMe), ethoxy (—OCH₂CH₃ or —OEt), t-butoxy (—O—C(CH₃)₃ or —OtBu) andthe like.

“Haloalkyl” is an alkyl group, as defined above, in which one or morehydrogen atoms of the alkyl group is replaced with a halogen atom. Thealkyl portion of a haloalkyl group can have 1 to 20 carbon atoms (i.e.,C₁-C₂₀ haloalkyl), 1 to 12 carbon atoms (i.e., C₁-C₁₂ haloalkyl), or 1to 6 carbon atoms (i.e., C₁-C₆ alkyl). Examples of suitable haloalkylgroups include, but are not limited to, —CF₃, —CHF₂, —CFH₂, —CH₂CF₃, andthe like. The term “haloalkyl” includes “polyfluoroalkyl”. The term“polyfluoroalkyl” is an alkyl group, as defined above, in which two ormore hydrogen atoms of the alkyl group is replaced with a fluorine atom.

“Alkenyl” is a hydrocarbon containing normal, secondary, tertiary orcyclic carbon atoms with at least one site of unsaturation, i.e. acarbon-carbon, sp² double bond. For example, an alkenyl group can have 2to 20 carbon atoms (i.e., C₂-C₂₀ alkenyl), 2 to 8 carbon atoms (i.e.,C₂-C₈ alkenyl), or 2 to 6 carbon atoms (i.e., C₂-C₆ alkenyl). Examplesof suitable alkenyl groups include, but are not limited to, ethylene orvinyl (—CH═CH₂), allyl (—CH₂CH═CH₂), cyclopentenyl (—C₅H₇), and5-hexenyl (—CH₂CH₂CH₂CH₂CH═CH₂).

“Alkynyl” is a hydrocarbon containing normal, secondary, tertiary orcyclic carbon atoms with at least one site of unsaturation, i.e. acarbon-carbon, sp triple bond. For example, an alkynyl group can have 2to 20 carbon atoms (i.e., C₂-C₂₀ alkynyl), 2 to 8 carbon atoms (i.e.,C₂-C₈ alkyne), or 2 to 6 carbon atoms (i.e., C₂-C₆ alkynyl). Examples ofsuitable alkynyl groups include, but are not limited to, acetylenic(—C≡CH), propargyl (—CH₂C≡CH), and the like.

“Alkylene” refers to a saturated, branched or straight chain or cyclichydrocarbon radical having two monovalent radical centers derived by theremoval of two hydrogen atoms from the same or two different carbonatoms of a parent alkane. For example, an alkylene group can have 1 to20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typicalalkylene radicals include, but are not limited to, methylene (—CH₂—),1,1-ethyl (—CH(CH₃)—), 1,2-ethyl (—CH₂CH₂—), 1,1-propyl (—CH(CH₂CH₃)—),1,2-propyl (—CH₂CH(CH₃)—), 1,3-propyl (—CH₂CH₂CH₂—), 1,4-butyl(—CH₂CH₂CH₂CH₂—), and the like.

“Alkenylene” refers to an unsaturated, branched or straight chain orcyclic hydrocarbon radical having two monovalent radical centers derivedby the removal of two hydrogen atoms from the same or two differentcarbon atoms of a parent alkene.

For example, and alkenylene group can have 1 to 20 carbon atoms, 1 to 10carbon atoms, or 1 to 6 carbon atoms. Typical alkenylene radicalsinclude, but are not limited to, 1,2-ethylene (—CH═CH—).

“Alkynylene” refers to an unsaturated, branched or straight chain orcyclic hydrocarbon radical having two monovalent radical centers derivedby the removal of two hydrogen atoms from the same or two differentcarbon atoms of a parent alkyne. For example, an alkynylene group canhave 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.Typical alkynylene radicals include, but are not limited to, acetylene(—C≡C—), propargyl (—CH₂C≡C—), and 4-pentynyl (—CH₂CH₂CH₂C≡C—).

“Amino” refers generally to a nitrogen radical which can be considered aderivative of ammonia, having the formula —N(X)₂, where each “X” isindependently H, substituted or unsubstituted alkyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,etc. The hybridization of the nitrogen is approximately sp³. Nonlimitingtypes of amino include —NH₂, —N(alkyl)₂, —NH(alkyl), —N(carbocyclyl)₂,—NH(carbocyclyl), —N(heterocyclyl)₂, —NH(heterocyclyl), —N(aryl)₂,—NH(aryl), —N(alkyl)(aryl), —N(alkyl)(heterocyclyl),—N(carbocyclyl)(heterocyclyl), —N(aryl)(heteroaryl),—N(alkyl)(heteroaryl), etc. The term “alkylamino” refers to an aminogroup substituted with at least one alkyl group. Nonlimiting examples ofamino groups include —NH₂, —NH(CH₃), —N(CH₃)₂, —NH(CH₂CH₃), —N(CH₂CH₃)₂,—NH(phenyl), —N(phenyl)₂, —NH(benzyl), —N(benzyl)₂, etc. Substitutedalkylamino refers generally to alkylamino groups, as defined above, inwhich at least one substituted alkyl, as defined herein, is attached tothe amino nitrogen atom. Non-limiting examples of substituted alkylaminoincludes —NH(alkylene-C(O)—OH), —NH(alkylene-C(O)—O-alkyl),—N(alkylene-C(O)—OH)₂, —N(alkylene-C(O)—O-alkyl)₂, etc.

“Aryl” means an aromatic hydrocarbon radical derived by the removal ofone hydrogen atom from a single carbon atom of a parent aromatic ringsystem. For example, an aryl group can have 6 to 20 carbon atoms, 6 to14 carbon atoms, or 6 to 10 carbon atoms. Typical aryl groups include,but are not limited to, radicals derived from benzene (e.g., phenyl),substituted benzene, naphthalene, anthracene, biphenyl, and the like.

“Arylalkyl” refers to an acyclic alkyl radical in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with an aryl radical. Typical arylalkyl groupsinclude, but are not limited to, benzyl, 2-phenylethan-1-yl,naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl,2-naphthophenylethan-1-yl and the like. The arylalkyl group can comprise7 to 20 carbon atoms, e.g., the alkyl moiety is 1 to 6 carbon atoms andthe aryl moiety is 6 to 14 carbon atoms.

“Arylalkenyl” refers to an acyclic alkenyl radical in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, but also an sp² carbon atom, is replaced with an arylradical. The aryl portion of the arylalkenyl can include, for example,any of the aryl groups disclosed herein, and the alkenyl portion of thearylalkenyl can include, for example, any of the alkenyl groupsdisclosed herein. The arylalkenyl group can comprise 8 to 20 carbonatoms, e.g., the alkenyl moiety is 2 to 6 carbon atoms and the arylmoiety is 6 to 14 carbon atoms.

“Arylalkynyl” refers to an acyclic alkynyl radical in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, but also an sp carbon atom, is replaced with an arylradical. The aryl portion of the arylalkynyl can include, for example,any of the aryl groups disclosed herein, and the alkynyl portion of thearylalkynyl can include, for example, any of the alkynyl groupsdisclosed herein. The arylalkynyl group can comprise 8 to 20 carbonatoms, e.g., the alkynyl moiety is 2 to 6 carbon atoms and the arylmoiety is 6 to 14 carbon atoms.

The term “substituted” in reference to alkyl, alkylene, aryl, arylalkyl,alkoxy, heterocyclyl, heteroaryl, carbocyclyl, etc., for example,“substituted alkyl”, “substituted alkylene”, “substituted aryl”,“substituted arylalkyl”, “substituted heterocyclyl”, and “substitutedcarbocyclyl”, unless otherwise indicated, means alkyl, alkylene, aryl,arylalkyl, heterocyclyl, carbocyclyl respectively, in which one or morehydrogen atoms are each independently replaced with a non-hydrogensubstituent. Typical substituents include, but are not limited to, —X,—R^(b), —O—, ═O, —OR^(b), —SR^(b), —S—, —NR^(b) ₂, —N+R^(b) ₃, ═NR^(b),—CX₃, —CN, —OCN, —SCN, —N═C═O, —NCS, —NO, —NO₂, ═N₂, —N₃, —NHC(═O)R^(b),—OC(═O)R^(b), —NHC(═O)NR^(b) ₂, —S(═O)₂—, —S(═O)₂OH, —S(═O)₂ R^(b),—OS(═O)₂OR^(b), —S(═O)₂NR^(b) ₂, —S(═O)R^(b), —OP(═O)(OR^(b))₂,—P(═O)(OR^(b))₂, —P(═O)(O—)₂, —P(═O)(OH)₂, —P(O)(OR^(b))(O—),—C(═O)R^(b), —C(═O)X, —C(S)R^(b), —C(O)OR^(b), —C(O)O—, —C(S)OR^(b),—C(O)SR^(b), —C(S)SR^(b), —C(O)NR^(b) ₂, —C(S)NR^(b) ₂,—C(═NR^(b))NR^(b) ₂, where each X is independently a halogen: F, Cl, Br,or I; and each R^(b) is independently H, alkyl, aryl, arylalkyl, aheterocycle, or a protecting group or prodrug moiety. Alkylene,alkenylene, and alkynylene groups may also be similarly substituted.Unless otherwise indicated, when the term “substituted” is used inconjunction with groups such as arylalkyl, which have two or moremoieties capable of substitution, the substituents can be attached tothe aryl moiety, the alkyl moiety, or both.

“Heterocycle” or “heterocyclyl” as used herein includes by way ofexample and not limitation those heterocycles described in Paquette, LeoA.; Principles of Modern Heterocyclic Chemistry (W. A. Benjamin, NewYork, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistryof Heterocyclic Compounds, A Series of Monographs” (John Wiley & Sons,New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and28; and J. Am. Chem. Soc. (1960) 82:5566. In one specific embodiment ofthe invention “heterocycle” includes a “carbocycle” as defined herein,wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have been replacedwith a heteroatom (e.g. O, N, or S). The terms “heterocycle” or“heterocyclyl” includes saturated rings, partially unsaturated rings,and aromatic rings (i.e., heteroaromatic rings). Substitutedheterocyclyls include, for example, heterocyclic rings substituted withany of the substituents disclosed herein including carbonyl groups. Anon-limiting example of a carbonyl substituted heterocyclyl is:

Examples of heterocycles include by way of example and not limitationpyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl,tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl,furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl,isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl,2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl,azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl,thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl,phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl,pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl,4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl,chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl,oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,isatinoyl, and bis-tetrahydrofuranyl:

By way of example and not limitation, carbon bonded heterocycles arebonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2,3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline. Still more typically, carbon bonded heterocycles include2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl,5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles arebonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine,2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline,3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline,piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of aisoindole, or isoindoline, position 4 of a morpholine, and position 9 ofa carbazole, or β-carboline. Still more typically, nitrogen bondedheterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl,1-pyrazolyl, and 1-piperidinyl.

“Heteroaryl” refers to an aromatic heterocyclyl having at least oneheteroatom in the ring. Non-limiting examples of suitable heteroatomswhich can be included in the aromatic ring include oxygen, sulfur, andnitrogen. Non-limiting examples of heteroaryl rings include all of thosearomatic rings listed in the definition of “heterocyclyl”, includingpyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl,thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl,thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl,pyridazyl, pyrimidyl, pyrazyl, etc.

“Carbocycle” or “carbocyclyl” refers to a saturated (i.e., cycloalkyl),partially unsaturated (e.g., cycloakenyl, cycloalkadienyl, etc.) oraromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbonatoms as a bicycle, and up to about 20 carbon atoms as a polycycle.Monocyclic carbocycles have 3 to 7 ring atoms, still more typically 5 or6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms, e.g.,arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10ring atoms arranged as a bicyclo [5,6] or [6,6] system, or spiro-fusedrings. Non-limiting examples of monocyclic carbocycles includecyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl,1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl,1-cyclohex-2-enyl, 1-cyclohex-3-enyl, and phenyl. Non-limiting examplesof bicyclo carbocycles includes naphthyl, tetrahydronapthalene, anddecaline.

“Carbocyclylalkyl” refers to to an acyclic akyl radical in which one ofthe hydrogen atoms bonded to a carbon atom is replaced with acarbocyclyl radical as described herein. Typical, but non-limiting,examples of carbocyclylalkyl groups include cyclopropylmethyl,cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl andcyclohexylmethyl.

“Heteroarylalkyl” refers to an alkyl group, as defined herein, in whicha hydrogen atom has been replaced with a heteroaryl group as definedherein. Non-limiting examples of heteroaryl alkyl include—CH₂-pyridinyl, —CH₂-pyrrolyl, —CH₂-oxazolyl, —CH₂-indolyl,—CH₂-isoindolyl, —CH₂-purinyl, —CH₂-furanyl, —CH₂-thienyl,—CH₂-benzofuranyl, —CH₂-benzothiophenyl, —CH₂-carbazolyl,—CH₂-imidazolyl, —CH₂-thiazolyl, —CH₂-isoxazolyl, —CH₂-pyrazolyl,—CH₂-isothiazolyl, —CH₂-quinolyl, —CH₂-isoquinolyl, —CH₂-pyridazyl,—CH₂-pyrimidyl, —CH₂-pyrazyl, —CH(CH₃)-pyridinyl, —CH(CH₃)-pyrrolyl,—CH(CH₃)-oxazolyl, —CH (CH₃)-indolyl, —CH(CH₃)-isoindolyl,—CH(CH₃)-purinyl, —CH(CH₃)-furanyl, —CH(CH₃)-thienyl,—CH(CH₃)-benzofuranyl, —CH(CH₃)-benzothiophenyl, —CH(CH₃)-carbazolyl—CH(CH₃)-imidazolyl, —CH(CH₃)-thiazolyl, —CH(CH₃)-isoxazolyl,—CH(CH₃)-pyrazolyl, —CH(CH₃)-isothiazolyl, —CH(CH₃)-quinolyl,—CH(CH₃)-isoquinolyl, —CH(CH₃)-pyridazyl, —CH(CH₃)-pyrimidyl,—CH(CH₃)-pyrazyl, etc.

The term “optionally substituted” in reference to a particular moiety ofthe compound of Formula I, Ib, Ic, II, IIb, IIc, III, IIIb, IIIc, IV, V,VI, or VIb-d (e.g., an optionally substituted aryl group) refers to amoiety wherein all substitutents are hydrogen or wherein one or more ofthe hydrogens of the moiety may be replaced by substituents such asthose listed under the definition of “substituted” or as otherwiseindicated.

The term “optionally replaced” in reference to a particular moiety ofthe compound of Formula I, Ib, Ic, II, IIb, IIc, III, IIIb, IIIc, IV, V,VI, or VIb-d (e.g., the carbon atoms of said (C₁-C₈)alkyl may beoptionally replaced by —O—, —S—, or —NR^(a)—) means that one or more ofthe methylene groups of the (C₁-C₈)alkyl may be replaced by 0, 1, 2, ormore of the groups specified (e.g., —O—, —S—, or —NR^(a)—).

The term “non-terminal carbon atom(s)” in reference to an alkyl,alkenyl, alkynyl, alkylene, alkenylene, or alkynylene moiety refers tothe carbon atoms in the moiety that intervene between the first carbonatom of the moiety and the last carbon atom in the moiety. Therefore, byway of example and not limitation, in the alkyl moiety—CH₂(C*)H₂(C*)H₂CH₃ or alkylene moiety —CH₂(C*)H₂(C*)H₂CH₂— the C* atomswould be considered to be the non-terminal carbon atoms.

The term “transition metal” or “transition element” is defined followingthe nomenclature of the Interantional Union of Pure and AppliedChemistry in the Compendium of Chemical Terminology, Internet edition.

The term “lanthanide” means the elements La, Ce, Pr, Nd, Pm, Sm, Eu, Gd,Tb, Dy, Ho, Er, Tm, Yb and Lu.

The term “alkaline earth or alkaline earth metal” means the elements Be,Mg, Ca, Sr, Ba and Ra.

The transition metals, lanthanides, alkaline earth metals and othermetals such as aluminum, gallium, indium, thallium, tin, lead or bismuthreferred to herein may form salts with acidic compounds. For example,they may form salts of triflic acid (CF₃SO₂OH). Many of these metals canexist in multiple oxidation states and thus form more than one salt withacid compounds. When reference is made to a salt of a metal, all suchoxidation states are contemplated as being included in this invention solong as they are stable oxidation states of the metal.

The term “treating”, in reference to the method claims described herein,means combining the reagents described in the claim under conditionswherein a reaction occurs. A non-limiting example is “treating acompound of Formula IIIb with a compound of Formula IV” would meancombining the compound of Formula IIIb with a compound of Formula IV”under conditions wherein the two molecules would react. The ordering ofthe combining step, i.e., adding a compound of Formula IIIb to acompound of Formula IV or adding a compound of Formula IV to a compoundof Formula IIIb, is dependent upon the substituents and stability of therespective compounds being combined. The choice of the order ofcombination would be well understood by one skilled in the art based onthe knowledge imparted with the instant disclosure. Both orders ofcombining the reagents are encompassed by the instant invention.

Unless otherwise specified, the carbon atoms of the compounds of FormulaI, Ib, Ic, II, IIb, IIc, III, IIIb, IIIc, IV, V, VI, or VIb-d areintended to have a valence of four. In some chemical structurerepresentations where carbon atoms do not have a sufficient number ofvariables attached to produce a valence of four, the remaining carbonsubstitutents needed to provide a valence of four should be assumed tobe hydrogen. For example,

has the same meaning as

“Protecting group” refers to a moiety of a compound that masks or altersthe properties of a functional group or the properties of the compoundas a whole. The chemical substructure of a protecting group varieswidely. One function of a protecting group is to serve as anintermediate in the synthesis of the parental drug substance. Chemicalprotecting groups and strategies for protection/deprotection are wellknown in the art. See: “Protective Groups in Organic Chemistry”,Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991. Protectinggroups are often utilized to mask the reactivity of certain functionalgroups, to assist in the efficiency of desired chemical reactions, e.g.making and breaking chemical bonds in an ordered and planned fashion.Protection of functional groups of a compound alters other physicalproperties besides the reactivity of the protected functional group,such as the polarity, lipophilicity (hydrophobicity), and otherproperties which can be measured by common analytical tools.

It is to be noted that all enantiomers, diastereomers, and racemicmixtures, tautomers, polymorphs, pseudopolymorphs of compounds withinthe scope of Formula I, Ib, Ic, II, IIb, IIc, III, IIIb, IIIc, IV, V,VI, or VIb-d and acceptable salts thereof are embraced by the presentinvention. All mixtures of such enantiomers and diastereomers are withinthe scope of the present invention.

A compound of Formula I, Ib, Ic, II, IIb, IIc, III, IIIb, IIIc, IV, V,VI, or VIb-d and acceptable salts thereof may exist as differentpolymorphs or pseudopolymorphs. As used herein, crystalline polymorphismmeans the ability of a crystalline compound to exist in differentcrystal structures. The crystalline polymorphism may result fromdifferences in crystal packing (packing polymorphism) or differences inpacking between different conformers of the same molecule(conformational polymorphism). As used herein, crystallinepseudopolymorphism means the ability of a hydrate or solvate of acompound to exist in different crystal structures. The pseudopolymorphsof the instant invention may exist due to differences in crystal packing(packing pseudopolymorphism) or due to differences in packing betweendifferent conformers of the same molecule (conformationalpseudopolymorphism). The instant invention comprises all polymorphs andpseudopolymorphs of the compounds of Formula I, Ib, Ic, II, IIb, IIc,III, IIIb, IIIc, IV, V, VI, or VIb-d and their acceptable salts.

A compound of Formula I, Ib, Ic, II, IIb, IIc, III, IIIb, IIIc, IV, V,VI, or VIb-d and acceptable salts thereof may also exist as an amorphoussolid. As used herein, an amorphous solid is a solid in which there isno long-range order of the positions of the atoms in the solid. Thisdefinition applies as well when the crystal size is two nanometers orless. Additives, including solvents, may be used to create the amorphousforms of the instant invention. The instant invention comprises allamorphous forms of the compounds of Formula I, Ib, Ic, II, IIb, IIc,III, IIIb, IIIc, IV, V, VI, or VIb-d and their acceptable salts.

The modifier “about” used in connection with a quantity is inclusive ofthe stated value and has the meaning dictated by the context (e.g.,includes the degree of error associated with measurement of theparticular quantity).

The compounds of the invention, exemplified by Formula I, Ib, Ic, II,IIb, IIc, III, IIIb, IIIc, IV, V, VI, or VIb-d may have chiral centers,e.g. chiral carbon or phosphorus atoms. The compounds of the inventionthus include racemic mixtures of all stereoisomers, includingenantiomers, diastereomers, and atropisomers. In addition, the compoundsof the invention include enriched or resolved optical isomers at any orall asymmetric, chiral atoms. In other words, the chiral centersapparent from the depictions are provided as the chiral isomers orracemic mixtures. Both racemic and diastereomeric mixtures, as well asthe individual optical isomers isolated or synthesized, substantiallyfree of their enantiomeric or diastereomeric partners, are all withinthe scope of the invention. The racemic mixtures are separated intotheir individual, substantially optically pure isomers throughwell-known techniques such as, for example, the separation ofdiastereomeric salts formed with optically active adjuncts, e.g., acidsor bases followed by conversion back to the optically active substances.In most instances, the desired optical isomer is synthesized by means ofstereospecific reactions, beginning with the appropriate stereoisomer ofthe desired starting material.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers may separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., NewYork. Many organic compounds exist in optically active forms, i.e., theyhave the ability to rotate the plane of plane-polarized light. Indescribing an optically active compound, the prefixes D and L or R and Sare used to denote the absolute configuration of the molecule about itschiral center(s). The prefixes d and 1, D and L, or (+) and (−) areemployed to designate the sign of rotation of plane-polarized light bythe compound, with S, (−), or 1 meaning that the compound islevorotatory while a compound prefixed with R, (+), or d isdextrorotatory. For a given chemical structure, these stereoisomers areidentical except that they are mirror images of one another. A specificstereoisomer may also be referred to as an enantiomer, and a mixture ofsuch isomers is often called an enantiomeric mixture. A 50:50 mixture ofenantiomers is referred to as a racemic mixture or a racemate, which mayoccur where there has been no stereoselection or stereospecificity in achemical reaction or process. The terms “racemic mixture” and “racemate”refer to an equimolar mixture of two enantiomeric species, devoid ofoptical activity.

The compounds of Formula I, Ib, Ic, II, IIb, IIc, VI, and VIb-d arenucleosides with an anomeric carbon atom at position 1 of thecarbohydrate ring. A non-limiting example would be Formula VIb whereinthe R¹⁷ substituent is in the 1 position of the carbohydrate. ThusFormula VIb is actually a representation of at least two compounds ofFormula VIb1 (β riboside) and VIb2 (α riboside) with respect to theanomeric carbon atom. It is intended that Formula I, Ib, II, IIb, VI,and VIb-d are inclusive of both anomeric carbon isomers.

The method of preparing a compound of Formula I, Ib or Ic from acompound of Formula II, IIb, or IIc, respectively, provides differentratios of the β riboside to α riboside depending upon the reactionconditions and particularly the Lewis acid used to promote the reaction.In preferred embodiments, the amount of β riboside exceeds the amount ofα riboside. In one preferred embodiment, the ratio of β riboside to αriboside is at least about 3:1; in another preferred embodiment, theratio is at least about 3.5:1; in another preferred embodiment, theratio is at least about 4:1; in another preferred embodiment, the ratiois at least about 5:1; in another preferred embodiment, the ratio is atleast about 6:1; in another preferred embodiment, the ratio is at leastabout 7:1; in another preferred embodiment, the ratio is at least about8:1; and in a particular preferred embodiment, the ratio is at least 9:1or more.

Whenever a compound described herein is substituted with more than oneof the same designated group, e.g., “R” or “R¹”, then it will beunderstood that the groups may be the same or different, i.e., eachgroup is independently selected. Wavy lines,

, indicate the site of covalent bond attachments to the adjoiningsubstructures, groups, moieties, or atoms.

The compounds of the invention can also exist as tautomeric isomers incertain cases. Although only one delocalized resonance structure may bedepicted, all such forms are contemplated within the scope of theinvention. For example, ene-amine tautomers can exist for purine,pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and alltheir possible tautomeric forms are within the scope of the invention.

One skilled in the art will recognize that thepyrrolo[1,2-f][1,2,4]triazinyl and imidazo[1,2-f][1,2,4]triazinylheterocycles can exist in tautomeric forms. For example, but not by wayof limitation, structures (a) and (b) can have equivalent tautomericforms as shown below:

All possible tautomeric forms of the heterocycles in all of theembodiments disclosed herein are within the scope of the invention.

All publications, patents, and patent documents cited herein above areincorporated by reference herein, as though individually incorporated byreference.

Examples

Certain abbreviations and acronyms are used in describing theexperimental details. Although most of these would be understood by oneskilled in the art, Table 1 contains a list of many of theseabbreviations and acronyms.

TABLE 1 List of abbreviations and acronyms. Abbreviation Meaning Ac₂Oacetic anhydride AIBN 2,2′-azobis(2-methylpropionitrile) Bnunsubstituted benzyl BnBr benzylbromide BSA bis(trimethylsilyl)acetamideBz benzoyl BzCl benzoyl chloride CDI carbonyl diimidazole DABCO1,4-diazabicyclo[2.2.2]octane DBN 1,5-diazabicyclo[4.3.0]non-5-ene DDQ2,3-dichloro-5,6-dicyano-1,4-benzoquinone DBU1,5-diazabicyclo[5.4.0]undec-5-ene DCA dichloroacetamide DCCdicyclohexylcarbodiimide DCM dichloromethane DMAP4-dimethylaminopyridine DME 1,2-dimethoxyethane DMTCl dimethoxytritylchloride DMSO dimethylsulfoxide DMTr 4,4′-dimethoxytrityl DMFdimethylformamide EtOAc ethyl acetate ESI electrospray ionization HMDShexamethyldisilazane HPLC High pressure liquid chromatography LDAlithium diisopropylamide LRMS low resolution mass spectrum MCPBAmeta-chloroperbenzoic acid MeCN acetonitrile MeOH methanol MMTC monomethoxytrityl chloride m/z or m/e mass to charge ratio MH⁺ mass plus 1MH⁻ mass minus 1 MsOH methanesulfonic acid MS or ms mass spectrum NBSN-bromosuccinimide PMB para-methoxybenzyl Ph phenyl rt or r.t. roomtemperature TBAF tetrabutylammonium fluoride TMSCl chlorotrimethylsilaneTMSBr bromotrimethylsilane TMSI iodotrimethylsilane TMSOTf(trimethylsilyl)trifluoromethylsulfonate TEA triethylamine TBAtributylamine TBAP tributylammonium pyrophosphate TBSClt-butyldimethylsilyl chloride TEAB triethylammonium bicarbonate TFAtrifluoroacetic acid TLC or tlc thin layer chromatography Trtriphenylmethyl Tol 4-methylbenzoyl Turbo Grignard 1:1 mixture ofisopropylmagnesium chloride and lithium chloride δ parts per milliondown field from tetramethylsilaneCompound 1c

Compound 1a (prepared according to J. Org. Chem., 1961, 26, 4605; 10.0g, 23.8 mmol) was dissolved in anhydrous DMSO (30 mL) and placed undernitrogen. Acetic anhydride (20 mL) was added, and the mixture wasstirred for 48 h at room temperature. When the reaction was complete byLC/MS, it was poured onto 500 mL ice water and stirred for 20 min. Theaqueous layer was extracted with ethyl acetate (3×200 mL). The organicextracts were combined and washed with water (3×200 mL). The aqueouslayers were discarded and the organic was dried over anhydrous MgSO₄ andevaporated to dryness. The residue was taken up in DCM and loaded onto asilica gel column. The final product 1b was purified by elution with 25%EtOAc/hexanes; 96% yield. ¹H-NMR (CD₃CN): δ □□3.63-3.75 (m, 2H), 4.27(d, 1H), 4.50-4.57 (m, 3H), 4.65 (s, 3H), 4.69-4.80 (m, 2H), 7.25 (d,2H), 7.39 (m, 13H).

7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (prepared according toWO2007/056170, 0.5 g, 2.4 mmol) was suspended in anhydrous THF (10 mL).Under nitrogen with stirring, TMSCl (0.668 mL, 5.28 mml) was added andthe mixture was stirred for 20 min. at room temperature. The reactionwas then cooled to −78° C. and a solution of BuLi (6.0 mL, 1.6 M inhexanes) was added slowly. The reaction was stirred for 10 min. at −78°C. and then a solution of the lactone 1b (1.0 g, 2.4 mmol in THF) wasadded via syringe. When the reaction was complete by LC/MS, acetic acid(0.5 mL) was added to quench the reaction. Solvents were removed byrotary evaporation and the residue was taken up in a mixture of 50:50dichloromethane/water (100 mL). The organic layer was collected andwashed with 50 mL additional water, dried over anhydrous MgSO₄ andfiltered. Evaporation and purification by column chromatography (0-50%EtOAc: hexanes) provided a 1:1 mixture of anomers ic; 25% yield. LC/MS(m/z: 553, M+H+).

Compound 2c

To a dry, argon purged round bottom flask (100 mL) were added anhydrousDMSO (6 mL) and anhydrous acetic anhydride (4 mL, 42.4 mmol). Compound2a (1.0 g, 2.3 mmol) was then added and the reaction mixture was allowedto stir at room temperature until complete disappearance of the startingmaterial. After 17 h, the flask was placed into an ice bath and sat.NaHCO₃ (6 mL) was added to neutralize the reaction mixture. The organicmaterial was then extracted using EtOAc (3×10 mL) and the combinedorganic layers were dried using MgSO₄. The solvent was removed underreduced pressure and the crude material was purified using flash silicagel chromatography (hexanes/EtOAc). 955 mg (96%) of the desired material2b was isolated. LC/MS=433.2 (M+H⁺). ¹H NMR (300 MHz, CDCl₃): δ 7.33 (m,15H), 4.80 (d, 1H), 4.64 (m, 6H), 4.06 (d, 1H), 3.79 (dd, 1H), 3.64 (dd,1H), 1.54 (s, 3H).

To a dry, argon purged round bottom flask (100 mL) were added7-bromo-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (234 mg, 1.10 mmol) andanhydrous THF (1.5 mL). TMSCl (276 μL, 2.2 mmol) was then added and thereaction mixture stirred for 2 h. The flask was placed into a dryice/acetone bath (˜−78° C.) and BuLi (2.5 mL, 4.0 mmol, 1.6 M inhexanes) was added dropwise. After 1 h, a solution of 2b (432 mg, 1.0mmol) in THF was cooled to 0° C. and then added to the reaction flaskdropwise. 5 After 1 h of stirring at −78° C., the flask was warmed to 0°C. and sat. NH₄Cl (5 mL) was added to quench the reaction. The organicswere extracted using EtOAc (3×10 mL) and the combined organic layerswere dried using MgSO₄. The solvent was removed under reduced pressureand the crude material was purified using flash silica gelchromatography (hexanes/EtOAc). 560 mg (90%) of the desired material 2cwas isolated. LC/MS=567.2 (M+H+). ¹H NMR (300 MHz, CDCl₃): δ 7.85 (m,1H), 7.27 (m, 15H), 7.01 (m, 1H), 6.51 (m, 1H), 4.66 (m, 8H), 4.40 (m,2H), 3.79 (m, 3H), 1.62 (s, 2′-CH₃ from the one anomer), 1.18 (s, 2′-CH₃from the other anomer).

Alternative Procedures for 2c

To a dry, argon purged round bottom flask were added7-bromo-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (9.6 g, 45 mmol) andanhydrous THF (60 mL). TMSCl (12.4 mL, 99 mmol) was then added and thereaction mixture stirred for 2 h. The flask was placed into a dryice/acetone bath (˜−78° C.) and BuLi (98 mL, 158 mmol, 1.6M in hexanes)was added dropwise. After 1 h, this reaction mixture was added to asolution of 2b (13.0 g, 30 mmol) in THF at −78° C. via cannula. After 2h of stirring at −78° C., the flask was warmed to 0° C. Saturated NH₄Cl(150 mL) was added to quench the reaction. The organics were extractedusing EtOAc (3×100 mL) and the combined organic layers were dried usingMgSO₄. The solvent was removed under reduced pressure and the crudematerial was purified using flash silica gel chromatography(hexanes/EtOAc). 7.5 g (44%) of the desired material 2c was isolated.LC/MS=567.2 (M+H+).

To a 500 ml jacketed 3-necked flask fitted with a thermocouple,vacuum/N₂ inlet and overhead stirring apparatus was added7-bromo-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (20 g, 1.0 equiv., 94mmol). This was suspended in dry THF (200 ml) and cooled to 0° C. Tothis was added dropwise 31 ml of MeMgCl solution (3M in THF, 1.0equiv.). This proceeded with bubbling and a significant exotherm. Therate of addition was controlled to maintain internal temperature below10° C. Following completion of addition and cooling to 0° C.,1,2-bis(chlorodimethylsilyl)ethane (20.2 g, 1.0 equiv.) was added in asingle portion, with exotherm to about 5° C. Once the temperature hadreturned to 0° C., a second portion of 31 ml MeMgCl (3M in THF, 1.0equiv.) was added as before. Once the temperature returned to 0° C., 80ml of iPrMgCl.LiCl solution (1.3 M in THF, 1.1 equiv.) was added. Theresulting dark solution was allowed to warm to room temperature, andconversion was checked by HPLC, with sample preparation in MeOH toprovide the des-bromo heterocycle. Once the conversion of7-bromo-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine was >95% complete (5hrs), the solution was cooled to 0° C., and a solution of 2b (40.6 g, 94mmol) in 100 ml THF was added via canulla. The resulting orange solutionwas allowed to warm to room temperature and stirred overnight. After 12hrs, the reaction was found to be complete by HPLC (sample prepared inH₂O/MeCN 1:1). At this point 200 ml of 13% NH₄Cl solution was added andbriskly stirred for 15 min. After this time, agitation was ceased, andthe two layers were allowed to separate. The organic layer was thenreduced to roughly 70 ml, and MeCN (100 ml) was added, followed by 300ml 1M aqueous HCl solution. The resulting slurry was stirred at roomtemperature for 2 hrs, then filtered through a sintered glass funnel.The resulting solid was dried overnight under vacuum at 45° C. to give2c. Yield 37.6 g (66%)

To a suspension of 7-bromo-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (2.14g, 10 mmol) in 0.5 M LiCl solution of anhydrous THF (20 mL) was addedTMSCl (2.53 mL, 20 mmol) and stirred at room temperature for 2 h. Aftercooling to −20° C., 3.0 M methyl magnesium chloride in diethyl ether(6.67 mL) was added dropwise while stirring. The mixture was thenallowed to warm to room temperature over a period of 1 h. After coolingback to −20° C., Turbo Grignard (1.3 M in THF) was added in portionsuntil the magnesium-bromine exchange was nearly complete (˜15.5 mL overa period of 2 h). A solution of 2b (5.2 g, 12 mmol) was then added. Theresulting mixture was allowed to warm to room temperature. The reactionwas quenched with methanol, affording 2c.

Compound 3a and 3b

To a suspension of7-bromo-2,4-bis-methylsulfanyl-imidazo[2,1-f][1,2,4]triazine (preparedaccording to WO2008116064, 600 mg, 2.06 mmol) in anhydrous THF (6 mL)was dropwise added BuLi (1.6 M in hexanes, 1.75 mL, 2.81 mmol) at −78°C. The suspension became red brown solution after 5 min, and then asolution of 2b (810 mg, 1.87 mmol) in THF (0.6 mL) was added dropwise tothe mixture. The mixture was then allowed to warm up to roomtemperature. After 30 min, saturated NH₄Cl was added to quench thereaction. The mixture was diluted with ethyl acetate; the organic layerwas washed with brine and concentrated in vacuo. The residue waspurified by silica gel column chromatography (˜40% EtOAc/hexanes),affording 3a as an isomeric mixture (0.77 g, 64%). MS=645.2 (M+H⁺).

Compound 3a (2.0 g, 3.10 mmol) was transferred to a steel bomb reactor,and cooled at −78° C. Liquid ammonia (˜20 mL) was collected at −78° C.and added to the bomb reactor. The bomb reactor was tightly sealed andwarmed up to room temperature. The mixture was then heated at 50° C. for20 h. Complete conversion occurred. After the ammonia gas was vented,the residue was purified by silica gel column chromatography(EtOAc/hexanes), affording the product 3b as a pale yellow solid (1.78g, 94%). MS=614.3 (M+H⁺).

Compound 4

To a suspension of 7-bromo-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (2.13g, 10 mmol) in THF (20 mL) was added TMSCl (2.66 mL, 21 mmol) andstirred at room temperature for 16 h under argon. After cooling to −78°C., a solution of BuLi (1.6 M, 21 mL, 33 mmol) in hexanes was addeddropwise. The mixture was stirred for 1 h at the same temperature. Asolution of 4a (prepared according to WO 200631725, 4.46 g, 12 mmol) inTHF (10 mL) was then added. After stirring for 2 h at −78° C., saturatedammonium chloride was added to quench the reaction. The mixture wasextracted with ethyl acetate. The organic extract was concentrated invacuo. The residue was purified by silica gel chromatography (ethylacetate/hexanes), affording 4 as a yellow solid (1.6 g, 32%). MS=507.1(M+H+).

Alternative Procedure for Compound 4 Using1,2-Bis-[(Chlorodimethyl)Silanyl]Ethane Instead of Chlorotrimethylsilane

To a suspension of 7-bromo-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (500mg, 2.35 mmol) in THF (6.5 mL) was added BuLi (1.6 M in hexanes, 1.6 mL)at −78° C. After 30 min., a solution of1,2-bis-[(chlorodimethyl)silanyl]ethane (538 mg, 2.4 mmol) in THF (1.2mL) was added. After 45 min., BuLi (1.6 mL) was added. After anadditional 30 min., BuLi (1.5 mL) was added. After 30 min., a solutionof 4a (610 mg, 1.64 mmol) in THF (2 mL) was then added dropwise. Theresulting mixture was stirred at −78° C. for 2 h under argon. Aceticacid (0.7 mL) was added dropwise to quench the reaction, followed byaddition of saturated ammonium chloride. The mixture was extracted withethyl acetate. The organic extract was concentrated in vacuo. Theresidue was purified by silica gel chromatography (ethylacetate/hexanes), affording 4 (320 mg, 40%). The starting 4a was alsorecovered (350 mg) from the chromatography.

Compound 5

To a suspension of7-bromo-2,4-bis-methylsulfanyl-imidazo[2,1-f][1,2,4]triazine (preparedaccording to WO2008116064, 500 mg, 1.72 mmol) in anhydrous THF (5 mL)was dropwise added BuLi (1.6 M in hexanes, 1.61 mL, 2.41 mmol) at −78OC. The suspension became red brown solution after 5 min, and then amixture of 4a (675 mg, 1.81 mmol) and boron trifluoride etherate (2.40mL, 1.89 mmol) in THF (5 mL) was added dropwise to the mixture. Afterstirring for 2 h at −78° C., saturated NH₄Cl was added to quench thereaction. The mixture was diluted with ethyl acetate; the organic layerwas washed with brine and concentrated in vacuo. The residue waspurified by silica gel column chromatography (EtOAc/hexanes), affording5 as a rich yellow foam (650 mg, 67%). ¹H NMR (400 MHz, CDCl₃): δ 8.13(d, 2H), 8.03 (d, 2H), 7.81 (d, 1H), 7.59 (t, 1H), 7.45 (m, 3H), 7.36(t, 2H), 6.40 (brs, 1H), 6.01 (dd, 1H), 4.78 (m, 2H), 4.60 (dd, 1H),2.68 (s, 3H), 2.45 (s, 3H), 1.62 (d, 3H). ¹⁹F NMR (376 MHz, CDCl₃): δ−167.5. MS=585.1 (M+H+).

Compound 6

To a suspension of sodium hydride (about 60% suspension in oil, 400 mg,10 mmol) in DMF (about 20 mL) is added dropwise a solution of 6a(prepared according to J. Chem. Soc., Perkin Trans 1, 1991, 490, about2.2 g, 10 mmol) in DMF (10 mL) at about 0° C. The mixture is thenstirred at about room temperature until the gas evolution ceases. Benzylbromide (about 1 eq.) is added and the mixture is stirred for about 1 to16 h at about 0 to 100° C. The mixture is poured into ice-water (300 mL)and extracted with ethyl acetate. The organic extract may be purified bysilica gel chromatography to give 6.

Compound 7

To a suspension of 7-bromo-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (about10 mmol) in THF (about 20 mL) is added TMSC1 (about 21 mmol) and themixture is stirred at about room temperature for about 1 to 16 h underargon. After cooling to about −78° C., a solution of BuLi (about 1.6 Min hexanes, about 33 mmol) is added dropwise. The mixture is stirred forabout ito 5 h at about the same temperature. A solution of 6 (about 12mmol) in THF (about 10 mL) is then added. After stirring for about 2 hat about −78° C., saturated ammonium chloride is added to quench thereaction. The mixture is extracted with ethyl acetate. The organicextract is concentrated in vacuo. The residue may be purified by silicagel chromatography (ethyl acetate/hexanes), to give 7.

Lactone B

20.0 g lactone A (123.4 mmol) is suspended in 200 mL iPrOAc and to thismixture is added 65 μL H₂SO₄ (1.23 mmol, 0.01 equiv.). This mixture iscooled to 15° C. To the cooled mixture is added 11.8 mL 2-methoxypropene(123.4 mmol, 1.0 equiv.) over a period of 2 h. Upon completion ofaddition the mixture is allowed to stir for 12 h at 15° C. Followingage, the mixture is warmed to 20° C. and another 6.0 mL 2-methoxypropene(0.5 equiv) is added to the reaction mixture. The mixture is aged withstirring at 20° C. for an additional 7 h. Following age, The solids areremoved by filtration, rinsed with 100 mL iPrOAc. The combined organicwashes are washed 1× with 100 mL water, and the organic layer isconcentrated to a colorless oil. This oil is diluted with 100 mLheptane, and upon concentration affords colorless solids, which arecollected by filtration, and rinsed with 100 mL heptane giving 8.36 g(36% yield) of desired compound, (M+H)/Z=203.

Lactone C

0.50 g lactone acetonide B (2.47 mmol), 0.294 mL benzyl bromide (2.47mmol, 1.0 equiv.) and 5.0 mL tetrahydrofuran are combined and themixture is cooled to 0° C. To the cooled mixture is added 2.47 mL of a1.0 M LiHMDS in THF solution (2.47 mmol, 1.0 equiv.) over a period of2.0 h. The mixture is allowed to slowly warm to 22° C., and is aged withstirring over 16 h. Following age, to the mixture is added 5.0 mL water,and the layers are split. The organic layer is concentrated, and the oilis purified by SiO₂ chromatography (0→40% EtOAc/Hexanes) affording 88.4mg desired product as a colorless oil, (M+H)/Z=293.

Lactone D

0.50 g lactone acetonide B (2.47 mmol), 0.335 mL PMBBr (2.47 mmol, 1.0equiv.) and 5.0 mL tetrahydrofuran are combined and the mixture iscooled to 0° C. To the cooled mixture is added 2.0 mL of a 1.0 M LiHMDSin THF solution (2.0 mmol, 0.8 equiv.) over a period of 2.0 h. Themixture is allowed to slowly warm to 22° C., and is aged with stirringover 16 h. Following age, the mixture is cooled to 0 C and to the cooledmixture is added the remaining 0.5 mL 1.0 M LiHMDS/THF solution (0.2equiv.) over a period of 40 min. Following completion of base addition,the mixture is warmed to 23 C and aged for 1 h with stirring. Followingage, the mixture is cooled to 0° C., and to the cooled mixture is added0.6 mL 4 N sulfuric acid solution, followed by 0.6 mL water, and theresulting layers are separated (aq. pH 9). The combined organic washesare concentrated to a colorless oil, and the oil is purified by SiO₂chromatography (0→40% EtOAc/Hexanes) affording 23.4 mg desired product Das a colorless oil, (M+H)/Z=323.

Lactone E

Lactone A (4.82 g, 29.7 mmol, 1.0 eq) was dissolved in 50 mL DMF.Imidazole (8.1 g, 119 mmol, 4 eq) was added. Triethylsilylchloride (17.9g, 119 mmol, 4 eq) was then added over ˜5 min and the mixture heated to50° C. 2 mL methanol was added to quench the reaction. 50 mL toluene wasadded and the mixture washed sequentially with 40 mL water, 2×30 mL 5%NaHCO₃, and 25 mL sat'd. NaCl. The organics were dried over Na₂SO₄,filtered and concentrated to 14 g of a crude oil. The oil was purifiedby silica gel chromatography eluting with 10% EtOAc:hexanes to yield 9 gof Lactone E, (M+H)/Z=505.

Lactone F

To a flask was charged NaH (1.60 g) and N,N-dimethylformamide (15 mL).The solution was cooled in an ice bath and lactone A (1.56 g) was addedin DMF (3 mL) followed by a wash with DMF (1 mL) and the ice bath wasremoved. After 1 h, DMF (5 mL) was added to promote better stirring. Themixture was placed in an ice bath and allyl bromide (3.7 mL) was addedand the ice bath removed. After stirring overnight the mixture wascooled in an ice bath and the reaction mixture carefully quenched withwater (10 mL). To the mixture was added EtOAc (65 mL) and afteragitation and separation the organics were washed with water and brine.The organics were dried over a mixture of Na₂SO₄ and MgSO₄,concentrated, and column purified on silica gel to give 1.1 g of thetri-allyl derivative, (M+H)/Z=283.

Lactone G

To a flask was charged NaH (1.7 g) and N,N-dimethylformamide (30 mL).The solution was cooled in an ice bath and Lactone A (1.57 g) was addedin DMF (4 mL) followed by a wash with DMF (1 mL). The ice bath wasremoved and after 1.5 h the reaction mixture was cooled in an ice bathand 3,3-dimethylallyl bromide (5.2 mL) was added. The ice bath removedand the reaction left to stir overnight. The reaction mixture was cooledto 0° C. and was quenched with saturated NH₄Cl (3 mL) followed bydiluting with water (27 mL) and EtOAc (100 mL). The organics were thenwashed with water and brine (30 mL each) and then dried over Na₂SO₄,filtered and concentrated. The residue was purified by columnchromatography on silica gel giving 1.42 g (40%) of the tri-prenylLactone G, (M+H)/Z=367.

Lactone H

To a flask was charged the Lactone B (1.99 g) and DMF (20 mL). To thesolution was added imidazole (1.00 g) and TBSCl (1.93 g) and the mixturewas left to stir overnight. The next day water (20 mL) and EtOAc (50 mL)were added. The organics were then separated and washed with brine (20mL), dried over Na₂SO₄, filtered and concentrated. The residue waspurified by column chromatography on silica gel giving 2.75 g (88%) ofthe Lactone H, (M+H)/Z=317.

Compound 9

Compound 9 may be synthesized in the same manner as 1c by substitutingCompound 8 (Ogura, et al. J. Org. Chem. 1972, 37, 72-75) for 1b in thereaction.

Compound 11

Compound 11 may be synthesized in the same manner as Ic by substitutingCompound 10 (Ogura, et al. J. Org. Chem. 1972, 37, 72-75) for 1b in thereaction.

Compound 13

Compound 13 may be synthesized in the same manner as Ic by substitutingCompound 12 (Camps, et al.; Tetrahedron 1982, 38, 2395-2402) for 1b inthe reaction.

Compound 14

To 7-bromo-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (0.501 g) and THF(31.5 mL) was added 1,2-bis(chloromethylsilyl)ethane (0.518 g). To thecloudy solution was added NaH (60% in mineral oil, 0.235 g). After 10minutes the solution was cooled in a −40° C. bath and nBuLi (2.16 M inhexanes, 3.6 mL) was added. After 13 min the lactone (1.031 g) was addedin THF (3 mL) followed by a wash with 0.1 mL of THF. After 3 h thereaction mixture was at −20° C. and was quenched with saturated NH₄Cl (3mL) followed by the addition of water (7 mL). The solution was left towarm to room temperature overnight. The next day EtOAc (32 mL) was addedand after separating the organics they were washed with water and brine(10 mL each). The organics were dried over Na₂SO₄, filtered,concentrated and the resulting residue purified by column chromatographyon silica gel giving 0.567 g (48%) of the tri-prenyl protected lactol14, (M+H)/Z=501.

Compound 15

Compound 15 may be synthesized in the same manner as Ic by substitutingthe t-butylsilyl lactone depicted (Alessandrini, et al.; J. CarbohydrateChem. 2008, 27, 322-344) for 1b in the reaction.

Compound 17

Compound 17 may be synthesized in the same manner as Ic by substitutingCompound 16 (Alessandrini, et al.; J. Carbohydrate Chem. 2008, 27,322-344) for 1b in the reaction.

Compound 19

Compound 19 may be synthesized in the same manner as Ic by substitutingCompound 18 (Piccirilli, et al.; Helvetica Chimica Acta 1991, 74,397-406) for 1b in the reaction.

Compound 20

Compound 1c (0.28 g, 0.51 mmol) was dissolved in anhydrousdichloromethane (10 mL) and placed under nitrogen. Trimethylsilylcyanide (0.35 mL) was added and the mixture was cooled to 0° C. Afterstirring for 10 min., boron trifluoride etherate (50 uL) was added andthe reaction was allowed to warm to room temperature. When the reactionwas complete by LC/MS, triethylamine was added to quench the reactionand solvents were removed by rotary evaporation. The residue was takenup in dichloromethane and loaded onto a silica gel column. A mixture ofanomers was eluted using a gradient of 0-75% ethyl acetate and hexanes;37% yield of 20. ¹H-NMR (300 MHz,CD₃CN): δ□□3.61-3.90 (m, 2H), 4.09-4.19(m, 2H), 4.30-4.88 (m, 7H), 4.96 (d, 0.5H), 5.10 (d, 0.5H), 6.41 (bs,2H), 6.73-6.78 (m, 1H), 6.81-6.88 (m, 1H), 7.17 (m, 2H), 7.39 (m, 13H),7.86 (s, 0.5H), 7.93 (s, 0.5H).

Alternative Preparation of Compound 4 Using Trimethylsilyl Triflate asthe Lewis Acid

Compound 1c (1.1 g, 2.0 mmol) was dissolved in anhydrous dichloromethane(35 mL) and placed under nitrogen. Trimethylsilyl cyanide (1.21 mL, 9.1mmol) was added and the mixture was cooled to 0° C. After stirring for10 min., trimethylsilyl triflate (2.0 mL, 11 mmol) was added. When thereaction was complete by LC/MS (˜2 h), dichloromethane (70 mL) was addedto dilute followed by saturated sodium bicarbonate (70 mL). The mixturewas stirred for 10 min. and the organic layer was collected byseparatory funnel. The aqueous layer was extracted with dichloromethane,which was combined with the first organic extract. The solvents wereremoved by rotary evaporation. The residue was taken up indichloromethane and loaded onto a silica gel column. A mixture ofanomers was eluted using a gradient of 0-75% ethyl acetate and hexanes;90% yield of 20.

Compound 21

To a solution of compound 2c (1 g, 1.77 mmol) in CH₂Cl₂ (20 mL) at 0° C.was added TMSCN (1.4 mL, 10.5 mmol) and BF₃-Et₂O (1 mL, 8.1 mmol). Thereaction mixture was stirred at 0° C. for 0.5 h, then at roomtemperature for additional 0.5 h. The reaction was quenched with NaHCO₃at 0° C., and diluted with CH₃CO₂Et. The organic phase was separated,washed with brine, dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by chromatography on silica gel, eluted withCH₃CO₂Et-hexanes (1:1 to 2:1), to give the desired compound 21 (620 mg,61%). MS=576.1 (M+H⁺).

Alternative Preparation of Compound 21

A flask was charged with 2c.HCl (53.2 g, 1 eq) and dichloromethane (530mL). The slurry was cooled to −16° C. and TMSOTf (17.5 mL, 1.1 eq) wascharged over 2 minutes while maintaining an internal temperature ←5° C.;the solution became homogeneous. When the reaction mixture was −14° C.the TMSCN (1.34 mL, 2.3 eq) was charged over 2 minutes. After 1 h, asolution of 10% (w/w) potassium carbonate/water (480 mL) was addedfollowed by 45% (w/w) potassium hydroxide/water (53 mL) whilemaintaining a temperature of <0° C. The mixture was warmed to 20° C. andafter the layers separated the organics were exchanged with acetonitrilefollowed by a wash with heptanes. The acetonitrile organics wereconcentrated and exchanged with DCM (200 mL) and concentrated to a foamgiving 48.6 g (95%) of Compound 21, (M+H)/Z=576.

Compound 22

To a solution of compound 4 (50 mg, 0.1 mmol) and TMSCN (67 uL, 0.5mmol) in acetonitrile (2.0 mL) at 0° C. was added TMSOTf (91 uL, 0.5mmol). The reaction mixture was stirred at room temperature for 1 h,then at 65° C. for 3 d. The reaction was quenched with saturated NaHCO₃at room temperature, and diluted with CH₃CO₂Et. The organic phase wasseparated, washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by RP-HPLC (acetonitrile/water),to give the desired compound 22 (28 mg, 54%). MS=516.1 (M+H⁺).

Alternative Preparation of Compound 22

To a stirred solution of 4 (5 g, 10 mmol) in 1,2-dichloroethane (300 mL,0.04M) under argon was added In(OTf)₃ (16.8 g, 30 mmol) and stirred for5 min. The reaction mixture was then heated to 45° C. TMSCN (8.0 mL, 60mmol) was added quickly. The reaction was allowed to progress overnight.The solvent was evaporated off, and the crude mixture was purified bysilica gel chromatography (with Hex:EtOAc as eluent), affording compound22 (˜5 g).

MS [M+H⁺]=516.3

Compound 23

Compound 23 may be prepared in the same manner as Compound 20 bysubstituting Compound 9 for 1c.

Compound 24

Compound 24 may be prepared in the same manner as Compound 20 bysubstituting Compound 11 for 1c.

Compound 25

Compound 25 may be prepared in the same manner as Compound 20 bysubstituting Compound 13 for 1c.

Compound 26

Compound 26 may be prepared in the same manner as Compound 20 bysubstituting Compound 15 for 1c.

Compound 27

Compound 27 may be prepared in the same manner as Compound 20 bysubstituting Compound 17 for 1c.

Compound 28

Compound 28 may be prepared in the same manner as Compound 20 bysubstituting Compound 19 for 1c.

Compound 29

Compound 29 may be prepared in the same manner as Compound 20 bysubstituting Compound 3a for 1c.

Compound 30

Compound 30 may be prepared in the same manner as Compound 20 bysubstituting Compound 3b for 1c.

Compound 31

Compound 31 may be prepared in the same manner as Compound 20 bysubstituting Compound 5 for Ic.

Alternative Preparation of Compound 31

Compound 31 may also be prepared in the same manner as Compound 20 bysubstituting Compound 37 for Ic.

Compound 32

Compound 32 may be prepared in the same manner as Compound 20 bysubstituting Compound 7 for 1c.

Compound 33

A solution of MCPBA (1.55 g, 8.96 mmol) in dichloromethane (20 mL) wasdropwise added to a solution of 3b (2.5 g, 4.07 mmol) in dichloromethane(40 mL) while stirring. The resulting mixture was stirred at roomtemperature until complete disappearance of the starting material. After3.5 h, the solvent was removed under reduced pressure and the crudematerial was purified using flash silica gel chromatography(hexanes/EtOAc). 2.0 g (77%) of the desired material 33 was isolated.LC/MS=646.2 (M+H+).

Compound 34

Compound 34 may be prepared in the same manner as Compound 20 bysubstituting Compound 33 for Ic.

Compound 35

Compound 34 (2.0 g, 3.10 mmol) was dissolved in dichloromethane (15 mL)in a round bottom flask (50 mL) and then transferred to a steel bombreactor. The solvent was removed under a positive flow of N₂ (g) and thesolid material was treated with liquid NH₃ at −78° C. The tightly sealedbomb reactor was placed into a preheated oil bath at 110° C. and thereaction continued to proceed for 14 h. 1.8 g (100%) of the desiredmaterial 35 was isolated using MeOH and was used as is for the nextreaction. LC/MS=583.3 (M+H⁺)

Compound 36

To a dry, argon purged round bottom flask (50 mL) were added3,4-bis-benzyloxy-5-benzyloxymethyl-2-(2,4-diamino-imidazo[2,1-f][1,2,4]triazin-7-yl)-3-methyl-tetrahydro-furan-2-ol35 (800 mg, 1.37 mmol) and anhydrous MeCN (18 mL). The flask was cooledto 0° C. and DBU (1.02 mL, 6.85 mmol) was added. After 5 min ofstirring, TMSOTf (1.49 mL, 8.22 mmol) was added to the flask followed bydropwise addition of TMSCN (1.10 mL, 8.22 mmol). The reaction mixturewas allowed to warm to room temperature and the flask was then equippedwith a reflux condenser and placed into a vessel preheated at 65° C.After 2 days of stirring, the flask was cooled to room temperature andthen placed into an ice bath and the reaction was quenched withsaturated NaHCO₃. EtOAc (3×10 mL) was used to extract the organicmaterial and the combined organic layers were washed with brine (3×10mL) and dried using MgSO₄. The solvent was removed under reducedpressure and the crude material was purified using flash chromatography(hexanes/EtOAc). 750 mg (93%) of the desired material 36 was isolated.LC/MS=592.3 (M+H⁺).

Compound 37

To a solution of 5 (300 mg, 0.51 mmol) in pyridine (1.5 mL) was addedacetic anhydride (0.29 mL, 3.08 mmol) and stirred at 120° C. for 16 h.After cooling to room temperature, ethyl acetate and water were added.The ethyl acetate layer was taken, washed with dilute HCl followed bysaturated ammonium chloride, dried over magnesium sulfate, andconcentrated. The residue was purified by silica gel chromatography(dichloromethane/ethyl acetate), affording two stereoisomers of 37.

For fast moving isomer of 37; 26 mg, ¹H NMR (400 MHz, CDCl₃): δ 8.39 (d,J=4.8 Hz, 1H), 8.00 (d, J=7.2 Hz, 2H), 7.98 (d, J=7.2 Hz, 2H), 7.59 (t,J=7.2 Hz, 1H), 7.51 (t, J=7.2 Hz, 1H), 7.45 (t, J=7.2 Hz, 2H), 7.38 (t,J=7.2 Hz, 2H), 6.39 (dd, J=8.2, 26.4 Hz, 1H), 5.61 (m, 1H), 4.77 (dd,J=2.6, 12.2 Hz, 1H), 4.25 (dd, J=4.8, 12.4 Hz, 1H), 2.68 (s, 3H), 2.61(s, 3H), 1.68 (d, J=22.8 Hz, 3H), 1.54 (s, 3H). MS=627.0 (M+H⁺).

For slow moving isomer of 37; 81 mg, ¹H NMR (400 MHz, CDCl₃): δ 8.06 (d,J=7.2 Hz, 2H), 7.98 (d, J=7.2 Hz, 2H), 7.81 (d, J=4.8 Hz, 1H), 7.60 (t,J=7.2 Hz, 1H), 7.51 (t, J=7.2 Hz, 1H), 7.45 (t, J=7.2 Hz, 2H), 7.35 (t,J=7.2 Hz, 2H), 6.00 (dd, J=8.6, 23.8 Hz, 1H), 4.91 (m, 1H), 4.77 (dd,J=4.0, 12.4 Hz, 1H), 4.52 (dd, J=4.2, 12.2 Hz, 1H), 2.64 (s, 3H), 2.52(s, 3H), 1.93 (s, 3H), 1.66 (d, J=22.4 Hz, 3H), MS=627.1 (M+H+).

Compound 38

To a 3-neck flask under filled with N₂ was added 441 mg (0.2 mmol, 0.25equiv.) Palladium (10% on C, Degussa type, 50% water content). This wassuspended in MeOH (7.5 ml, 15 vol.), and then 500 mg (0.83 mmol, 1equiv.) 2c-HCl was added. The reaction was placed under light vacuum,then under a H₂ atmosphere. After being stirred vigorously overnight,the reaction was found to be complete. The reaction mixture was filteredthrough celite, which was then rinsed several times with MeOH. The MeOHwas removed under rotary evaporation, and the resulting oil was taken upin EtOAc, giving a white precipitate. This was filtered, providingCompound 38. Yield: 248 mg (90%), (M+H)/Z=297.

Compound 39

1.0 g of 39a (3.08 mmol) is combined with 10.0 mL pyridine (124.78 mmol)and 4.76 mL (N,O-bis(trimethylsilyl)trifluoroacetamide+1% TMSClsolution; 18.50 mmol, 6.0 equiv.). The mixture is heated to 80° C., andaged for on hour. Following 1.0 h age, the homogeneous yellow solutionis cooled to 23° C., and aged with stirring for 18 h. Following aging,to the solution is added 10.0 mL toluene, and the mixture isconcentrated by vacuum distillation to an orange oil. The oil isdissolved in 10.0 mL dichloromethane, and the solution is cooled to −10°C. To this cooled solution is added dropwise 2.51 mL TMSOTf (13.88 mmol,4.5 equiv.) over a period of 30 min. Following TMSOTf addition, themixture is aged at −5.0 C for 5 min. Following aging, 2.31 mL TMSCN(18.50 mmol, 6.0 equiv.) is added over 8 min. following TMSCN addition,the mixture is warmed to 23° C., and aged with stirring for 2.0 h.Following aging, the mixture is added to a solution of 7.0 g 25 wt %NaOMe/MeOH solution (32.0 mmol, 10.7 equiv.) cooled to 0° C. Followingneutralization. the resulting mixture is concentrated to a viscous redoil. This oil is dissolved in 25 mL EtOAc, and to this solution is added10 mL heptane. The precipitated solids are filtered, and washed with 20mL EtOAc. The combined rinse and liquors are concentrated and purifiedby SiO₂ chromatography to afford the desired compound as a mixture ofisomers, (M+H)/Z=306.

Compound 40

0.10 g 40a (0.232 mmol) is combined with 200.1 mg triethylamine (1.92mmol, 6.0 equiv.) is suspended in 1.0 mL dichloromethane and thismixture is cooled to −5.0° C. To this heterogeneous suspension is added470 μL TMSOTf (8.0 equiv.) over a period of 3 minutes with stirring. Themixture is aged @−5.0° C. for 10 minutes with stirring. Following age,to the cooled mixture is added 240 μL TMSCN (6.0 equiv.). The mixture isaged with stirring at 0° C. for an additional 2 h. The desired compound40 is formed in ˜50% by ANHPLC, (M+H)/Z=666.

Compounds 41-45

Using either Lactone C, D, E, F or H, Compounds 41, 42, 43, 44, or 45,respectively, may be prepared using the procedures described to prepareCompounds 2c or 14.

Compounds 46-51

Using Compounds 41, 42, 43, 44, 45 or 14, respectively, Compounds 46,47, 48, 49, 50 or 51, respectively, may be obtained using the cyanationprocedures described for the examples disclosed herein.

All publications, patents, and patent applications cited herein aboveare incorporated by reference herein, as though individuallyincorporated by reference.

The invention has been described with reference to various specific andpreferred embodiments and techniques. However, one skilled in the artwill understand that many variations and modifications may be made whileremaining within the spirit and scope of the invention.

What is claimed is:
 1. A compound that is

or an acceptable salt thereof.